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Key Role for Glia in Stroke Uncovered

Wed, 13 Mar 2013 00:00:00 -0400

BOSTON (March 18, 2013) — New research published in the Journal of Neuroscience suggests that modifying signals sent by astrocytes, our star-shaped brain cells, may help to limit the spread of damage after an ischemic brain stroke. The study in mice, by neuroscientists at Tufts University School of Medicine, determined that astrocytes play a critical role in the spread of damage following stroke.

The National Heart Foundation reports that ischemic strokes account for 87% of strokes in the United States. Ischemic strokes are caused by a blood clot that forms and travels to the brain, preventing the flow of blood and oxygen.

Even when blood and oxygen flow is restored, however, neurotransmitter processes in the brain continue to overcompensate for the lack of oxygen, causing brain cells to be damaged. The damage to brain cells often leads to health complications including visual impairment, memory loss, clumsiness, moodiness, and partial or total paralysis.

Research and drug trials have focused primarily on therapies affecting neurons to limit brain cell damage. Phil Haydon’s group at Tufts University School of Medicine have focused on astrocytes, a lesser known type of brain cell, as an alternative path to understanding and treating diseases affecting brain cells.

In animal models, his research team has shown that astrocytes—which outnumber neurons by ten to one—send signals to neurons that can spread the damage caused by strokes. The current study determines that decreasing astrocyte signals limits damage caused by stroke by regulating the neurotransmitter pathways after an ischemic stroke.

The research team compared two sets of mice: a control group with normal astrocyte signaling levels and a group whose signaling was weakened enough to be made protective rather than destructive. To assess the effect of astrocyte protection after ischemic strokes, motor skills, involving tasks such as walking and picking up food, were tested. In addition, tissue samples were taken from both groups and compared.

“Mice with altered astrocyte signaling had limited damage after the stroke,” said first author Dustin Hines, PhD, a post-doctoral scholar in the department of neuroscience at Tufts University School of Medicine. “Manipulating the astrocyte signaling demonstrates that astrocytes are critical to understanding the spread of damage following stroke.”

“Looking into ways to utilize and enhance the astrocyte’s protective properties in order to limit damage is a promising avenue in stroke research,” said senior author Phillip Haydon, PhD Haydon is the Annetta and Gustav Grisard professor and chair of the department of neuroscience at Tufts University School of Medicine and a member of the neuroscience program faculty at the Sackler School of Graduate Biomedical Sciences at Tufts.

Research reported in this publication was supported by the National Institute of Neurological Disorders and Stroke and the National Institute of Mental Health, both of the National Institutes of Health under award numbers R01NS037585 and R01MH095385, respectively. Dustin Hines was partially funded by the Heart and Stroke Foundation of Canada. Haydon is the co-founder and president of GliaCure Inc., which has licensed a pending patent application filed by Tufts University related to work described in this paper.

Hines DJ, Haydon PG. 2013. Inhibition of a SNARE-sensitive pathway in astrocytes attenuates damage following stroke. J Neurosci. 33: 4234-4240.

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you are a member of the media interested in learning more about this topic, or speaking with a faculty member at Tufts University School of Medicine or another Tufts health sciences researcher, please contact Siobhan Gallagher at 617-636-6586.

Sackler Team Discovers Phage Immune System

Wed, 27 Feb 2013 13:28:00 -0500

BOSTON (February 27, 2013, 1:00 pm ET) — A study published today in the journal Nature reports that a viral predator of the cholera bacteria has stolen the functional immune system of bacteria and is using it against its bacterial host. The study provides the first evidence that this type of virus, the bacteriophage (“phage” for short), can acquire a wholly functional and adaptive immune system.

The phage used the stolen immune system to disable – and thus overcome – the cholera bacteria’s defense system against phages. Therefore, the phage can kill the cholera bacteria and multiply to produce more phage offspring, which can then kill more cholera bacteria. The study has dramatic implications for phage therapy, which is the use of phages to treat bacterial diseases. Developing phage therapy is particularly important because some bacteria, called superbugs, are resistant to most or all current antibiotics.

Until now, scientists thought phages existed only as primitive particles of DNA or RNA and therefore lacked the sophistication of an adaptive immune system, which is a system that can respond rapidly to a nearly infinite variety of new challenges. Phages are viruses that prey exclusively on bacteria and each phage is parasitically mated to a specific type of bacteria. This study focused on a phage that attacks Vibrio cholerae, the bacterium responsible for cholera epidemics in humans.

Howard Hughes Medical Institute investigator Andrew Camilli, Ph.D., of Tufts University School of Medicine led the research team responsible for the surprising discovery.

First author Kimberley D. Seed, PhD, a postdoctoral fellow in Camilli’s lab, was analyzing DNA sequences of phages taken from stool samples from patients with cholera in Bangladesh when she identified genes for a functional immune system previously found only in some bacteria (and most Archaea, a separate domain of single-celled microorganisms).

To verify the findings, the researchers used phage lacking the adaptive immune system to infect a new strain of cholera bacteria that is naturally resistant to the phage. The phage were unable to adapt to and kill the cholera strain. They next infected the same strain of cholera bacteria with phage harboring the immune system, and observed that the phage rapidly adapted and thus gained the ability to kill the cholera bacteria. This work demonstrates that the immune system harbored by the phage is fully functional and adaptive.

“Virtually all bacteria can be infected by phages. About half of the world’s known bacteria have this adaptive immune system, called CRISPR/Cas, which is used primarily to provide immunity against phages. Although this immune system was commandeered by the phage, its origin remains unknown because the cholera bacterium itself currently lacks this system. What is really remarkable is that the immune system is being used by the phage to adapt to and overcome the defense systems of the cholera bacteria. Finding a CRISPR/Cas system in a phage shows that there is gene flow between the phage and bacteria even for something as large and complex as the genes for an adaptive immune system,” said Seed.

“The study lends credence to the controversial idea that viruses are living creatures, and bolsters the possibility of using phage therapy to treat bacterial infections, especially those that are resistant to antibiotic treatment,” said Camilli, professor of Molecular Biology & Microbiology at Tufts University School of Medicine and member of the Molecular Microbiology program faculty at the Sackler School of Graduate Biomedical Sciences at Tufts University.

Camilli’s previous research established that phages are highly prevalent in stool samples from patients with cholera, implying that phage therapy is happening naturally and could be made more effective. In addition, a study published by Camilli in 2008 determined that phage therapy works in a mouse model of cholera intestinal infection.

The team is currently working on a study to understand precisely how the phage immune system disables the defense systems of the cholera bacteria. This new knowledge will be important for understanding whether the phage’s immune system could overcome newly acquired or evolved phage defense systems of the cholera bacteria, and thus has implications for designing an effective and stable phage therapy to combat cholera.

Additional authors are David W. Lazinski, PhD, senior research associate in the Camilli lab at Tufts University School of Medicine, and Stephen B. Calderwood, MD, Morton N. Swartz, MD academy professor of medicine at Harvard Medical School, and chief, division of infectious disease and vice-chair, department of medicine at Massachusetts General Hospital.

Research reported in this publication was supported by the National Institute of Allergies and Infectious Diseases of the National Institutes of Health under award numbers R01AI55058, R01AI045746, and R01AI058935.

Seed KD, Lazinski DW, Calderwood SB, Camilli A. 2013. A bacteriophage encodes its own CRISPR/Cas adaptive response to evade host innate immunity. Nature 494: 489-491.

Sackler Group Identifies Possible Target for Depression Therapy

Tue, 22 Jan 2013 00:00:00 -0500

BOSTON (January 23, 2013) — Neuroscience researchers from Tufts University have found that our star-shaped brain cells, called astrocytes, may be responsible for the rapid improvement in mood in depressed patients after acute sleep deprivation. This in vivo study, published in the current issue of Translational Psychiatry, identified how astrocytes regulate a neurotransmitter involved in sleep. The researchers report that the findings may help lead to the development of effective and fast-acting drugs to treat depression, particularly in psychiatric emergencies.

Drugs are widely used to treat depression, but often take weeks to work effectively. Sleep deprivation, however, has been shown to be effective immediately in approximately 60% of patients with major depressive disorders. Although widely-recognized as helpful, it is not always ideal because it can be uncomfortable for patients, and the effects are not long-lasting.

During the 1970s, research verified the effectiveness of acute sleep deprivation for treating depression, particularly deprivation of rapid eye movement sleep, but the underlying brain mechanisms were not known.

Most of what we understand of the brain has come from research on neurons, but another type of largely-ignored cell, called glia, are their partners. Although historically thought of as a support cell for neurons, the Phil Haydon group at Tufts University School of Medicine has shown in animal models that a type of glia, called astrocytes, affect behavior.

Haydon’s team had established previously that astrocytes regulate responses to sleep deprivation by releasing neurotransmitters that regulate neurons. This regulation of neuronal activity affects the sleep-wake cycle. Specifically, astrocytes act on adenosine receptors on neurons. Adenosine is a chemical known to have sleep-inducing effects.

During our waking hours, adenosine accumulates and increases the urge to sleep, known as sleep pressure. Chemicals, such as caffeine, are adenosine receptor antagonists and promote wakefulness. In contrast, an adenosine receptor agonist creates sleepiness.

“In this study, we administered three doses of an adenosine receptor agonist to mice over the course of a night that caused the equivalent of sleep deprivation. The mice slept as normal, but the sleep did not reduce adenosine levels sufficiently, mimicking the effects of sleep deprivation. After only 12 hours, we observed that mice had decreased depressive-like symptoms and increased levels of adenosine in the brain, and these results were sustained for 48 hours,” said first author Dustin Hines, PhD, a post-doctoral fellow in the department of neuroscience at Tufts University School of Medicine (TUSM).

“By manipulating astrocytes we were able to mimic the effects of sleep deprivation on depressive-like symptoms, causing a rapid and sustained improvement in behavior,” continued Hines.

“Further understanding of astrocytic signaling and the role of adenosine is important for research and development of anti-depressant drugs. Potentially, new drugs that target this mechanism may provide rapid relief for psychiatric emergencies, as well as long-term alleviation of chronic depressive symptoms,” said Naomi Rosenberg, PhD, dean of the Sackler School of Graduate Biomedical Sciences and vice dean for research at Tufts University School of Medicine. “The team’s next step is to further understand the other receptors in this system and see if they, too, can be affected.”

Senior author, Phillip G. Haydon, PhD, is the Annetta and Gustav Grisard professor and chair of the department of neuroscience at Tufts University School of Medicine (TUSM). Haydon is also a member of the neuroscience program faculty at the Sackler School of Graduate Biomedical Sciences at Tufts.

Additional authors are Luke I. Schmitt, BS, a PhD candidate in neuroscience at the Sackler School; Rochelle M. Hines, PhD, a post-doctoral fellow in the department of neuroscience at TUSM; and Stephen J. Moss, PhD, a professor of neuroscience at Tufts University School of Medicine and a member of the neuroscience program faculty at the Sackler School.

Hines DJ, Schmitt LI, Hines RM, Moss SJ, Haydon PG. 2013. Antidepressant effects of sleep deprivation require astrocyte-dependent adenosine mediated signaling. Transl Psychiatry Epub ahead of print.

This research was supported by award number R01MH095385 from the National Institute of Mental Health, part of the National Institutes of Health, as well as by award number R01NS037585 from the National Institute of Neurological Disorders and Stroke, both of the National Institutes of Health. Dustin Hines was partially funded by the Heart and Stroke Foundation of Canada. Haydon is co-founder and president of GliaCure Inc., which has licensed a pending patent application filed by Tufts University claiming compounds that modulate the signaling cascades, and related methods of use, described in this paper.

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If you are a member of the media interested in learning more about this topic, or speaking with a faculty member at the Tufts University School of Medicine or another Tufts health sciences researcher, please contact Siobhan Gallagher at 617-636-6586.

Key Role for Mitochondria in Inflammation Suggested

Mon, 17 Dec 2012 00:00:00 -0500

BOSTON (December 17, 2012) — Many illnesses, including psoriasis, include inflammatory responses that occur without an apparent infection and worsen with stress. In a study using cultured human mast cells in vitro and in rats, researchers from Tufts University School of Medicine and the Sackler School of Graduate Biomedical Sciences at Tufts University identified mitochondrial particles — secreted from live, activated mast cells — as a possible trigger of the inflammation that is common in such illnesses.

Mast cells are a part of the immune system and can secrete inflammatory molecules, such as histamine, in response to allergens and other triggers. Generated in the bone marrow, mast cells play vital roles in acquired and innate immunity within tissues in the body. Little is known about their secretory process except that energy generated by mitochondria is required.

When a person contracts an infection or has an allergic reaction, mast cells normally secrete molecules that alert the immune system to the presence of a foreign invader. These molecules trigger the body’s responses in order to contain and eliminate the infection or alert the body to initiate an inflammatory response. After this process, the mast cell regenerates. The research team sought to understand how inflammation could be triggered without the presence of an infection or allergen.

In the study, mast cells were stimulated by triggers secreted from nerves, rather than by infection or allergen. As a result, the mast cells secreted their inflammation-causing molecules, as well as some mitochondrial components. The mitochondrial components were secreted outside the cell into the extracellular fluid, but the mast cells retained their viability, indicating that the secretion of mitochondrial particles was not due to cell damage or death. The extracellular mitochondrial components then stimulated other skin cells to mount an auto-inflammatory response.

Purified human mitochondrial components were also injected into peripheral tissue of rats. Within four hours, they were detected in the blood, which suggests that mitochondrial components secreted in tissues can reach the systemic circulation, the part of the cardiovascular system that carries blood from the heart to the rest of the body.

“The immune system misread the mitochondrial components as an infectious agent, and there was inflammation as a result,” said first author Bodi Zhang, MD, MPH, PhD, graduate of the biochemistry program at the Sacker School. “Our study findings are different from a report last year suggesting that mitochondrial particles are released from damaged cells in patients with severe trauma. Additional studies are needed to gain a better understanding of this process.”

“Our work provides a possible explanation for inflammation that arises without apparent disease or injury,” said senior author Theoharis C. Theoharides, MS, MD, PhD, professor of molecular physiology and pharmacology at Tufts University School of Medicine and member of the Biochemistry, and Pharmacology & Experimental Therapeutics graduate program faculties at the Sackler School. “Secretion of mitochondrial components by immune cells may constitute an ‘innate pathogen’ that may stimulate self-response by the immune system.”

“Although this study does not identify the inflammatory mechanism that is common among auto-inflammatory illnesses, the findings help to lay a foundation for further research and may lead to new biomarkers and novel treatment targets,” Theoharides added.

This research was supported in part by grants to Theoharides from the National Institute of Arthritis and Musculoskeletal and Skin Diseases of the National Institutes of Health under award number R01AR47652 and by Safe Minds. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Tufts University has filed a patent application related to these findings.

Additional authors on the study are Shahrzad Asadi, PharmD, postdoctoral scholar in the Theoharides laboratory; Zuyi Weng, BS, graduate student in the Pharmacology & Experimental Therapeutics program at the Sackler School working in Dr. Theoharides’ laboratory; and Nikolaos Sismanopoulos, MD, formerly a postdoctoral fellow in the Theoharides’ laboratory and now at St. Elizabeth’s Medical Center. The authors have declared that no competing interests exist.

Zhang B, Asadi S, Weng Z, Sismanopoulos N, Theoharides TC. 2012. Stimulated human mast cells secrete mitochondrial components that have autocrine and paracrine inflammatory actions. PLoS ONE 7: e49767. Epub ahead of print.

Genetic Variant Linked to Decreased Heart Disease

Fri, 14 Dec 2012 00:00:00 -0500

BOSTON (December 14, 2012) – Scientists at the Jean Mayer USDA Human Nutrition Research Center on Aging (HNRCA) at Tufts University have discovered a new gene mechanism that appears to regulate triglyceride levels. This pathway may protect carriers of a gene variant against cardiovascular disease, especially among those with greater intakes of polyunsaturated fat (PUFA). The findings, published online this week in the American Journal of Human Genetics, contribute to research efforts to develop gene-specific diets that could potentially improve general health and complement chronic disease prevention and treatment.

The authors analyzed data from more than 27,000 men and women enrolled in ten epidemiological studies conducted in the United States and Europe that comprise the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium. Focusing on the Single Nucleotide Polymorphism (SNP) rs13702, they observed that a type of small RNA known as microRNA (miR), impacts production of lipoprotein lipase (LPL), an enzyme that mediates the metabolism of circulating triglycerides.

“We saw no miR activity in carriers of the gene variant,” said senior author José M. Ordovás, senior scientist and director of the Nutritional Genomics Laboratory at the HNRCA at Tufts University. “In the majority of the subjects the miR appeared to attach to the messenger RNA (mRNA), slowing down the manufacturing of LPL. Without that interference, people with the variant would presumably have more LPL available to breakdown excess triglycerides and prevent them from being deposited in the arteries, which could eventually lead to atherosclerosis and other cardiovascular diseases.”

The authors also noted lower triglyceride levels and higher concentrations of high-density lipoprotein (HDL) cholesterol, the so-called “healthy” cholesterol in association with the gene variant. Furthermore, carriers tended to have even lower triglyceride blood levels if they had higher PUFA intake.

“Based on the data, carriers of the gene variant may be able to further reduce their risk for cardiovascular disease by increasing their PUFA intake,” said Kris Richardson, Ph.D., a USDA Agricultural Research Service (ARS) post-doctoral associate in the Nutritional Genomics Laboratory and a recent graduate of Genetics PhD Program of the Sackler School of Graduate Biomedical Sciences at Tufts University. “To build on our observational data, future studies might investigate the effect of treating human cells in culture with PUFA to determine if it will mediate LPL levels through the identified miR.”

PUFA, found in foods such as salmon and vegetable oils, is considered a healthier fat. The current U.S. Dietary Guidelines for Americans recommend replacing saturated fats with the more beneficial PUFA and monounsaturated fats whenever possible.

José M. Ordovás is also a professor at the Friedman School of Nutrition Science and Policy at Tufts University and a member of the Genetics and Pharmacology & Experimental Therapeutics Graduate Faculty at the Sackler School.

This study is funded by grants from USDA and the National Heart, Lung and Blood Institute (NHLBI), award number P50 HL105185-01. A complete list of funding sources is available in the supplemental data portion of the paper.

Richardson, K, et al. 2013. Gain-of-function lipoprotein lipase variant rs13702 modulates lipid traits through disruption of a microRNA-410 seed site. Am J Hum Genet. Epub ahead of print.

Sackler Investigators Shed Light on Origins of Anxiety

Wed, 22 Aug 2012 15:11:00 -0400

BOSTON (August 22, 2012) — A study in mice conducted by researchers at Tufts University School of Medicine suggests that a woman’s risk of anxiety and dysfunctional social behavior may depend on the experiences of her parents, particularly fathers, when they were young. The study, published online in Biological Psychiatry, suggests that stress caused by chronic social instability during youth contributes to epigenetic changes in sperm cells that can lead to psychiatric disorders in female offspring across multiple generations.

“The long-term effects of stress can be pernicious. We first found that adolescent mice exposed to chronic social instability, where the cage composition of mice is constantly changing, exhibited anxious behavior and poor social interactions through adulthood. These changes were especially prominent in female mice,” said first author Lorena Saavedra-Rodríguez, PhD, postdoctoral fellow in the Larry Feig laboratory at Tufts University School of Medicine.

The researchers then studied the offspring of these previously-stressed mice and observed that again female, but not male, offspring exhibited elevated anxiety and poor social interactions. Notably, even though the stressed males did not express any of these altered behaviors, they passed on these behaviors to their female offspring after being mated to non-stressed females. Moreover, the male offspring passed on these behaviors to yet another generation of female offspring.

“We are presently searching for biochemical changes in the sperm of stressed fathers that could account for this newly appreciated form of inheritance” said senior author Larry A. Feig, PhD, professor of biochemistry at Tufts University School of Medicine and member of the biochemistry and neuroscience program faculties at the Sackler School of Graduate Biomedical Sciences at Tufts University. “Hopefully, this work will stimulate efforts to determine whether similar phenomena occur in humans.”

This research was supported by award numbers AA019317 from the National Institute on Alcohol Abuse and Alcoholism, and MH083324 from the National Institute of Mental Health, both part of the National Institutes of Health (NIH). The research was also supported by award number NS047243 from National Institute of Neurological Disorders and Stroke (NIH) to the Tufts Center for Neuroscience Research.

Saavedra-Rodríguez L, Feig LA. 2012. Chronic social instability induces anxiety and defective social interactions across generations. Biol Psych. Epub ahead of print.

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Sackler Faculty Contribute to TUSM High School Students and Teachers Program

Tue, 07 Aug 2012 19:54:00 -0400

BOSTON (August 3, 2012) - Tufts University School of Medicine today celebrated the achievements of the 33 Massachusetts high school students who participated in the School’s 2012 Teachers and High School Student Program. The program is one of Tufts’ signature initiatives to encourage high school students with diverse backgrounds to explore their interest in medicine and biomedical sciences. Established in 1989, the Tufts program supports the careers of aspiring young doctors and scientists by engaging them in a range of clinical and research opportunities across the Tufts Health Sciences campus in Boston.

“Tufts University is committed to nurturing scientific curiosity among young people of diverse backgrounds, particularly those from communities that are underrepresented in medicine and the health sciences,” said Harris Berman, M.D., dean of Tufts University School of Medicine. “The extraordinary students who participated in our high school program this summer have contributed immeasurably to the Tufts community, and we are proud to offer high school students the opportunity to launch promising careers as health professionals.”

“Our summer program for high school students offers invaluable experience to young people who might not otherwise have opportunities to explore their budding interests in medicine and the biomedical sciences,” said Joyce Sackey, M.D., dean for multicultural affairs and global health and associate professor at Tufts University School of Medicine. “Tufts’ Teachers and High School Students Program is one of our key initiatives to support the educational development of youth in our community.”

Selected high school students participated in a seven-week program and spent up to 25 hours each week in various positions at Tufts University School of Medicine, Tufts University School of Dental Medicine, Sackler Graduate School of Biomedical Sciences at Tufts or Tufts Medical Center. Students also took a gross anatomy course taught by Tufts medical students and gained knowledge of laboratory-based science; in the process, students developed relationships with medical and graduate student mentors that Tufts expects will continue beyond the summer program.

The Tufts program also includes an independent study, the findings of which the students presented to the Tufts community, family and friends today. Participating students and their projects were:

Edward Akubude (Mattapan), 16, Concord-Carlisle Regional High School “Reduction of OCD Symptoms in Mice”
Carlos Angeles (Norton), 19, Xaverian Brothers High School “The Relationship Between Diabetes and Diet”
Christina Augustin (Medford), 16, Prospect Hill Academy Charter School “The Effects of Marijuana on Pregnancy”
Janika Beatty (Malden), 17, Community Charter School of Cambridge “The Effects of Marijuana on Pregnancy”
Carrington Cazeau (Boston), 16, Natick High School “Zebrafish Fin Mutations”
Walter Chacon (Lynn), 16, Phillips Academy Andover “The Relationship Between Obesity and Depression”
Malka Forman (Brighton), 17, Maimonides School “Lower Limb Ischemic Threshold with Near Infrared Spectrometry Device”
John Frazer (Quincy), 16, Boston College High School “Evidence Based Review of Domestic Violence” (The reporting and recognition by healthcare providers of child abuse and neglect in the Latino population)”
Ericka Garcia (Brookline) 15, Brookline High School “Leukemia in Children”
Bryant Gill (Foxboro), 17, Xaverian Brothers High School “Correlation of Neuronal Signal to Astrocyte Morphology”
Nathan Gill (Foxboro), 16, Xaverian Brothers High School “Reduction of OCD symptoms in Mice”
Yvonne Hamisi (Springfield), 18, Baystate-Springfield Educational Partnership “Cardiac Differences Between Athletes and Non-Athletes”
Elyane James (Dorchester), 18, Marblehead High School “Evidence Based Review of Domestic Violence” (The reporting and recognition by healthcare providers of child abuse and neglect in the Latino population)”
Hyunji Koo (North Andover), 16, Phillips Academy Andover “Cross-cultural Communication and the Doctor-Patient Relationship”
Fatima Khan (Somerville), 16, Prospect Hill Academy Charter School “Abdominal Aortic Aneurysms”
Ryan Kuehl (Springfield), 18, Baystate-Springfield Educational Partnership “Too Much Exercise?”
Anthony “Nino” Lambert (Hanover), 16, Boston College High School “Factors That Affect the Concentration of Serine”
Jessica Mar (Brighton), 16, Boston Latin School “Physician Wellness”
Abby Mendez (Roxbury), 17, City on a Hill “Evidence Based Review of Domestic Violence (The reporting and recognition by healthcare providers of child abuse and neglect in the Latino population)”
Jasmine Ngan (Somerville), 16, Prospect Hill Academy Charter School “The Effects of Storage Conditions on Bloodspot Amino Acids”
Blessing Ojini (Roxbury), 16, Needham High School “The Benefits of Play in Child Development”
Emanuel Parrilla (Springfield), 18, Baystate-Springfield Educational Partnership “The Effects of a Torn ACL in Later Life”
Klarissa Ramkissoon (Milton), 17, Milton High School “Behavioral Testing in Mice”
Krystina San Soucie (Upton), 16, Nipmuc Regional High School “Methods to Maximize Serine Levels”
Abdullahi Tahlil (Roxbury), 17, Match High School “Child Health Assessment Mapping Project”
Lisa Tam (Boston), 18, John D. O'Bryant High School of Math and Science “Effectiveness of Home Visits Compared with Standard Care”
Dorothy Tran (Boston), 17, The Winsor School “Child Health Assessment Mapping Project”
Arianna Unger (Newton), 17, Maimonides School “A Comparative Study of Two Orthotic Systems Used for the Assisted Ambulation of a Child with Spina Bifida”
Camille Van Allen (Milton), 17, Milton High School “Benefits of Breast Feeding”
Winnie Wang (Boston), 18, Boston Latin School “Relationship Between Toxic/Nutritional and Leber's Hereditary Optic Neuropathy”
Natalie Wolanski (Springfield), 17, Baystate-Springfield Educational Partnership “Concussions in Sports and Society”
Davonte Willis (Quincy), 18, Quincy High School “Factors That Affect the Concentration of Amine Acids”
Kavin Zhu (Boston), 17, Boston Latin School “Genetic Disease as Exemplified by Hunter Syndrome”

The Teachers and High School Students Program is one of a number of “pipeline” programs at Tufts University School of Medicine designed to engage diverse students interested in the fields of medicine and biomedical sciences. Tufts offers programs for diverse students in middle school, high school, and college, as well as college graduates.

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If you are a member of the media interested in learning more about this topic, or speaking with a faculty member at Tufts University, please contact Jennifer Kritz at 617-636-3707 or Siobhan Gallagher at (617) 636-6586.

Sackler Team Probes Effect of Traumatic Brain Injury

Tue, 24 Jul 2012 17:40:00 -0400

BOSTON (July 24, 2012, 5:00PM EST) — A study, performed in mice and utilizing post-mortem samples of brains from patients with Alzheimer’s disease, found that a single event of a moderate-to-severe traumatic brain injury (TBI) can disrupt proteins that regulate an enzyme associated with Alzheimer’s. The paper, published in The Journal of Neuroscience, identifies the complex mechanisms that result in a rapid and robust post-injury elevation of the enzyme, BACE1, in the brain. These results may lead to the development of a drug treatment that targets this mechanism to slow the progression of Alzheimer’s disease.

“A moderate-to-severe TBI, or head trauma, is one of the strongest environmental risk factors for Alzheimer’s disease. A serious TBI can lead to a dysfunction in the regulation of the enzyme BACE1. Elevations of this enzyme cause elevated levels of amyloid-beta, the key component of brain plaques associated with senility and Alzheimer’s disease,” said first author Kendall Walker, PhD, postdoctoral associate in the department of neuroscience at Tufts University School of Medicine (TUSM).

Building on her previous work, neuroscientist Giuseppina Tesco, MD, PhD, of Tufts University School of Medicine (TUSM), led a research team that first used an in vivo model to determine how a single episode of TBI could alter the brain. In the acute phase (first two days) following injury, levels of two intracellular trafficking proteins (GGA1 and GGA3) were reduced, and an elevation of BACE1 enzyme level was observed.

Next, in an analysis of post-mortem brain samples from patients with Alzheimer’s disease, the researchers found that GGA1 and GGA3 levels were reduced while BACE1 levels were elevated in the brains of Alzheimer’s disease patients compared to the brains of people without Alzheimer’s disease, suggesting a possible inverse association.

In an additional experiment using a mouse strain genetically modified to express the reduced level of GGA3 that was observed in the brains of Alzheimer’s disease patients, the team found that one week following traumatic brain injury, BACE1 and amyloid-beta levels remained elevated even when GGA1 levels had returned to normal. The research suggests that reduced levels of GGA3 were solely responsible for the increase in BACE 1 levels and therefore the sustained amyloid-beta production observed in the sub-acute phase, or seven days, after injury.

“When the proteins are at normal levels, they work as a clean-up crew for the brain by regulating the removal of BACE1 enzymes and facilitating their transport to lysosomes within brain cells, an area of the cell that breaks down and removes excess cellular material. BACE1 enzyme levels may be stabilized when levels of the two proteins are low, likely caused by an interruption in the natural disposal process of the enzyme,” said Tesco, assistant professor of neuroscience at Tufts School of Medicine and member of the neuroscience program faculty at the Sackler School of Graduate Biomedical Sciences at Tufts.

“We found that GGA1 and GGA3 act synergistically to regulate BACE1 post-injury. The identification of this interaction may provide a drug target to therapeutically regulate the BACE1 enzyme and reduce the deposition of amyloid-beta in Alzheimer’s patients,” she continued. “Our next steps are to confirm these findings in post-mortem brain samples from patients with moderate-to-severe traumatic brain injuries.”

Moderate-to-severe TBIs are caused most often by traumas, such as severe falls or motor vehicle accidents, that result in a loss of consciousness. Not all traumas to the head result in a TBI. According to the Centers for Disease Control and Prevention, each year 1.7 million people sustain a TBI. Concussions, the mildest form of a TBI, account for about 75% of all TBIs. Studies have linked repeated head trauma to brain disease and some previous studies have linked single events of brain trauma to brain disease, such as Alzheimer’s. Alzheimer’s disease currently affects as many as 5.1 million Americans and is the most common cause of dementia in adults age 65 and over.

Additional authors on the study are Eugene Kang, MPH, research assistant in the department of neuroscience at TUSM; Michael Whalen, MD, PhD, Neuroscience Center and department of pediatrics at Massachusetts General Hospital and associate professor at Harvard Medical School; and Yong Shen, MD, PhD, of the Center for Advanced Therapeutic Strategies for Brain Disorders at Roskamp Institute.

This study was supported by grants from the National Institute on Aging (R01AG033016 and R01AG025952), part of the National Institutes of Health; and a grant from the Cure Alzheimer’s Fund.

Walker KR, Kang EL, Whalen MJ, Shen Y, Tesco G. 2012. Depletion of GGA1 and GGA3 mediates post-injury elevation of BACE1. J Neurosci. Epub ahead of print.

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If you are a member of the media interested in learning more about this topic or speaking with a faculty member at the Tufts University School of Medicine or another Tufts health sciences researcher, please contact Jennifer Kritz at 617-636-3707.

Sackler Team Gains Insight on Candida Pathogenesis

Tue, 24 Jul 2012 00:00:00 -0400

BOSTON (July 24, 2012) - The opportunistic fungal pathogen Candida albicans inconspicuously lives in our bodies until it senses that we are weak, when it quickly adapts to go on the offensive. The fungus, known for causing yeast and other minor infections, also causes a sometimes-fatal infection known as candidemia in immunocompromised patients. An in vivo study, published in mBio, demonstrates how C. albicans can distinguish between a healthy and an unhealthy host and alter its physiology to attack.

“The ability of the fungus to sense the immune status of its host may be key to its ability to colonize harmlessly in some people but become a deadly pathogen in others,” said Jessica V. Pierce, BA, PhD student in the molecular microbiology program at the Sackler School of Graduate Biomedical Sciences at Tufts.

“Effective detection and treatment of disease in immunocompromised patients could potentially work by targeting the levels of a protein, Efg1p, that we found influenced the growth of Candida albicans inside the host,” she continued.

The researchers knew from previous research that Efg1p influences the expression of genes that regulate how harmful a fungal cell can become. Surprisingly, the investigators found that lower Efg1p levels allow the fungal cells to grow to high levels inside a host. Higher levels of the protein result in less growth.

To examine how the immune status could affect the growth of C. albicans within a host, the researchers fed both healthy and immunocompromised mice equal amounts of two fungal strains containing two different levels of the Efg1p protein.

Fecal pellets from the mice were tested to determine which strain of fungi thrived. In a healthy host, the fungal cells with higher levels of the protein predominated.

In immunocompromised mice, the fungal cells with lower levels of the protein flourished. The researchers noted that lack of interactions with immune cells in the intestinal tract most likely caused the necessary environmental conditions favoring fungal cells that express lower levels of the protein, resulting in fungal overgrowth and setting the stage for systemic infection.

“By having a mixed population with some high Efg1p cells and some low Efg1p cells, the fungus can adjust its physiology to remain benign or become harmful when it colonizes hosts with varying immune statuses. These findings are important because they provide the first steps toward developing more effective methods for detecting and treating serious and stubborn infections caused by Candida albicans, such as candidemia,” said Carol A. Kumamoto, PhD, professor of molecular biology and microbiology at Tufts University School of Medicine and member of the molecular microbiology and genetics program faculties at the Sackler School of Graduate Biomedical Sciences.

The immune system and “good bacteria” within the body act to regulate the size of C. albicans fungal populations in healthy individuals. When the immune system is compromised, the fungus can spread throughout the body. Candidemia, i.e. blood-borne Candida, is the fourth most common blood infection among hospitalized patients in the United States and is found in immunocompromised patients such as babies, those with catheters, and the critically ill.

mBio is an online-only, open access journal published in association with the American Society for Microbiology.

This research was supported in part by grants AI076156, AI08179, and AI07422 from the National Institute of Allergy and Infectious Diseases, part of the National Institutes of Health.

Pierce JV, Kumamoto CA. 2012. Variation in Candida albicans EFG1 expression enables host-dependent changes in colonizing fungal populations mBio 3: e00117-12.

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If you are a member of the media interested in learning more about this topic, or speaking with a faculty member at the Tufts University School of Medicine, the Sackler School or another Tufts health sciences researcher, please contact Jennifer Kritz at 617-636-3707.

Bachovchin Work on Cancer Drug Highlighted

Wed, 04 Apr 2012 18:10:00 -0400

Sackler Team Sheds Light on Epigenetics and Stem Cell Regulation

Wed, 14 Mar 2012 00:00:00 -0400

Boston (March 14, 2012)

A research team has identified epigenetic signatures, markers on DNA that control transient changes in gene expression, within reprogrammed skin cells. These signatures can predict the expression of a wound-healing protein in reprogrammed skin cells or induced pluripotent stem cells (iPSCs), cells that take on embryonic stem cell properties. Understanding how the expression of the protein is controlled brings us one step closer to developing personalized tissue regeneration strategies using stem cells from a patient, instead of using human embryonic stem cells. The study was published in the Journal of Cell Science.

When skin cells are reprogrammed, many of their cellular properties are recalibrated as they aquire stem cell properties and then are induced to become skin cells again. In order for these “induced” stem cells to be viable in treatment for humans (tissue regeneration, personalized wound healing therapies, etc.), researchers need to understand how they retain or even improve their characteristics after they are reprogrammed.

Since the initial discovery of reprogramming, scientists have struggled with the unpredictability of the cells due to the many changes that occur during the reprogramming process. Classifying specific epigenetic signatures, as this study did, allows researchers to anticipate ways to produce cell types with optimal properties for tissue repair while minimizing unintended cellular abnormalities.

The researchers used reprogrammed cells to generate three-dimensional connective tissue that mimics an in vivo wound repair environment. To verify the role of the protein (PDGFRbeta) in tissue regeneration and maintenance, the team blocked its cellular expression, which impaired the cells’ ability to build tissue.

“We determined that successful tissue generation is associated with the expression of PDGFRbeta. Theoretically, by identifying the epigenetic signatures that indicate its expression, we can determine the reprogrammed cells’ potential for maintaining normal cellular characteristics throughout development,” said first author Kyle Hewitt, PhD, a graduate of the cell, molecular & developmental biology program at the Sackler School of Graduate Biomedical Sciences, and postdoctoral associate in the Garlick laboratory at Tufts University School of Dental Medicine (TUSDM).

“The ability to generate patient-specific cells from the reprogrammed skin cells may allow for improved, individualized, cell-based therapies for wound healing. Potentially, these reprogrammed cells could be used as a tool for drug development, modeling of disease, and transplantation medicine without the ethical issues associated with embryonic stem cells,” said senior author Jonathan Garlick, DDS, PhD, a professor in the department of oral and maxillofacial pathology and director of the division of tissue engineering and cancer biology at TUSDM.

Jonathan Garlick is also a member of the cell, molecular & developmental biology program faculty at the Sackler School at Tufts and the director of the Center for Integrated Tissue Engineering at TUSDM.

Additional authors of the study are Yulia Shamis, MSc, a PhD candidate in the cell, molecular, and developmental biology program at the Sackler School; Elana Knight, BSc, and Avi Smith, BA, both research technicians in the Garlick laboratory; Anna Maione, a PhD student in the cell, molecular & developmental biology program at the Sackler School, and Addy Alt-Holland, PhD, MSc, assistant professor at TUSDM.

This work was supported by grant # DE017413 to Dr. Garlick from the National Institute for Dental and Craniofacial Research, part of the National Institutes of Health.

Hewitt KJ, Shamis Y, Knight E, Smith A, Maione A, Alt-Holland A, Garlick JA. 2012. PDGFRβ expression and function in fibroblasts derived from pluripotent cells is linked to DNA demethylation. J Cell Sci. Epub ahead of print.

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If you are a member of the media interested in learning more about this topic, or speaking with a faculty member at the Tufts University School of Dental Medicine, the Sackler School, or another Tufts health sciences researcher, please contact Siobhan Gallagher at 617-636-6586.

Breakthrough in Wound Healing

Thu, 23 Feb 2012 00:00:00 -0500

BOSTON (February 23, 2012, 5:00 pm ET)

Researchers have combined bioactive peptides to successfully stimulate wound healing. The in vitro and in vivo study, published today in PLoS ONE, demonstrates that the combination of two peptides stimulates the growth of blood vessels and promotes re-growth of tissue. Further development of these peptides could lead to a new treatment for chronic and acute wounds.

The team tested a newly-created peptide, UN3, in pre-clinical models aimed to simulate impaired wound healing as is seen in patients with peripheral vascular diseases or uncontrolled diabetes. The peptide led to a 50% increase in blood vessel wall development, a 250% increase in growth of blood vessels, and a 300% increase in cell migration in response to the injury.

“Using double-blinded in vivo experiments, we then applied the wound-healing peptide UN3 with a peptide created during a previous study, named comb1. We found that, together, the two out-performed all control groups, including the only FDA-approved growth factor-containing drug for treating diabetic wounds, becaplermin,” said first author, Tatiana Demidova-Rice, PhD, now a graduate of the cell, molecular and developmental biology program at the Sackler School of Graduate Biomedical Sciences.

In December 2010, Herman and Demidova-Rice identified several peptides from a Clostridium histolyticum collagenase treatment of bio-synthesized extracellular matrix. The investigators then went on to cull key peptides and, from these, they created the peptide, comb1, possessing several strategic features, including its ability to stimulate angiogenesis by increasing blood vessel growth by 200% in vitro.

The second wound-healing peptide, UN3, identified in the current study, was created and modified from two naturally occurring peptides that are normally present in trace amounts and found in human platelet-rich plasma.

“The confirmation that these peptides could act synergistically to improve human wound healing moves our research one significant step closer to clinical application. We hope that someday soon, we may be able to help transform the way in which wound care is being delivered in civilian and combat settings,” said Ira Herman, PhD, professor of molecular physiology and pharmacology at Tufts University School of Medicine. Professor Herman is director, molecular and cellular physiology graduate program at the Sackler School of Graduate Biomedical Sciences and director, Center for Innovations in Wound Healing Research, Tufts University.

“The wound-healing peptides should also prove strategic as we continue developing ‘smart’ devices or fully-vascularized living tissue constructs for burn patients or those patients suffering with diabetic plantar or venous stasis ulcers. Clinical trials using the peptides will be the next step,” Herman continued. Tufts University has filed patent applications related to the wound-healing peptides.

Tufts Center for Innovations in Wound Healing Research brings together experts from Tufts’ medical, dental, veterinary and engineering schools, as well as Tufts Medical Center and local research institutes with a focus on creating innovative wound healing therapeutics as well as fully-vascularized organ constructs for personalized regenerative medicine.

Demidova-Rice is now at the Edwin L. Steele Laboratory for Tumor Biology in the department of Radiation Oncology at Massachusetts General Hospital. Additional authors include Lindsey Wolf, BS, formerly a research assistant at TUSM, now a graduate student working towards a PhD degree in the department of molecular genetics and microbiology at the University of Texas at Austin; Jeffry Deckenback, PhD, who was a postdoctoral fellow in the Herman lab while the work was being carried out; and Michael R. Hamblin, PhD, a principal investigator at the Wellman Center for Photomedicine at Massachusetts General Hospital and associate professor in the department of dermatology at Harvard Medical School.

This research was supported in part by grants # EY15125 and # EY19533 from the National Eye Institute, part of the National Institutes of Health, and Wound Care Partners, LLC.

Demidova-Rice TN, Wolf L, Deckenback J, Hamblin MR, Herman IM. Human platelet-rich plasma- and extracellular matrix-derived peptides promote impaired cutaneous would healing in vivo. PLoS ONE, Epub ahead of print.

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Tissue Engineering Leads to Cancer Breakthroughs

Wed, 11 Jan 2012 00:00:00 -0500

BOSTON (January 11, 2012)

New research demonstrates that previous models used to examine cancer may not be complex enough to accurately mimic the true cancer environment. Using oral cancer cells in a three-dimensional model of lab-made tissue that mimics the lining of the oral cavity, the researchers found that the tissue surrounding cancer cells can epigenetically mediate, or temporarily trigger, the expression or suppression of a cell adhesion protein associated with the progression of cancer. These new findings support the notion that drugs that are currently being tested to treat many cancers need to be screened using more complex tissue-like systems, rather than by using conventional petri dish cultures that do not fully manifest features of many cancers.

“Research on cancer progression has been drawn largely using models that grow cancer cells in plastic dishes. Our research reveals a major shortcoming in the experimental systems used to study cancer development. When using simplified culture systems in which cells are grown on plastic, cancer cells grow as a two dimensional monolayer and lack the three-dimensional tissue structure seen in human cancer. As a result, complex interactions that occur between the cancer cells and the surrounding tissue layers are not accounted for,” said first author Teresa DesRochers, PhD, a graduate of the Sackler School of Graduate Biomedical Sciences at Tufts, currently in the department of biomedical engineering at Tufts University School of Engineering.

The researchers report that the three-dimensional network of cell interactions activates epigenetic mechanisms that control whether genes critical for cancer development will be turned on or off. By imitating the structure of the tumor microenvironment seen in different stages of cancer, the research team was able to observe that cell-to-cell interactions that are inherent in tissue structure are sufficient to turn on the cell adhesion protein, E-cadherin, a molecule that can delay cancer development.

Since both invasion and metastasis occur when cells break away from the primary cancer site, an event correlated with loss of E-cadherin, treating cancers to induce re-expression of this protein through epigenetic control may be an important way to control cancer progression.

“Our findings show the reversible nature of E-cadherin when cancer cells are placed in a three-dimensional network of cells that mimics the way cancer develops in our tissues. This confirms that cancer biology needs to move into the “third dimension” where cancer cells can be studied in a network of other cells that can control their behavior. We know now that the plastic dish alone is not good enough,” said senior author Jonathan Garlick, DDS, PhD, a professor in the oral and maxillofacial pathology department at Tufts University School of Dental Medicine.

Jonathan Garlick is also a member of the Cell, Molecular & Developmental Biology program faculty at the Sackler School at Tufts and the director of the Center for Integrated Tissue Engineering (CITE) at Tufts University School of Dental Medicine.

This study, published in the January issue of Epigenetics, was performed in collaboration with Laurie Jackson-Grusby, PhD, associate in pathology at Children’s Hospital, Boston, and assistant professor at Harvard Medical School. Additional authors of the study are Yulia Shamis, MSc, a PhD student at the Sackler School of Graduate Biomedical Sciences; Addy Alt-Holland, MSc, PhD, an assistant professor at Tufts University School of Dental Medicine; Yasusei Kudo, DDS, PhD, and Takashi Takata, DDS, PhD, both of the department of oral and maxillofacial pathobiology, Graduate School of Biomedical Sciences, Hiroshima University, Japan; and Guangwen Wang, PhD, previously a fellow at Children’s Hospital Boston, now a senior scientist at Stemgent.

This research was supported in part by grant DE017143 from the National Institute of Dental and Craniofacial Research, part of the National Institutes of Health.

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If you are a member of the media interested in learning more about this topic, or speaking with a faculty member at the Tufts University School of Medicine, the Sackler School of Graduate Biomedical Sciences, or another Tufts health sciences researcher, please contact Siobhan Gallagher at 617-636-6586.

Sackler Faculty Uncover New Stress Regulation Mechanisms

Tue, 13 Dec 2011 00:00:00 -0500

BOSTON (December 13, 2011)

Neuroscience researchers from Tufts have demonstrated, for the first time, that the physiological response to stress depends on neurosteroids acting on specific receptors in the brain, and they have been able to block that response in mice. This breakthrough suggests that these critical receptors may be drug therapy targets for control of the stress-response pathway. This finding may pave the way for new approaches to manage a wide range of neurological disorders involving stress.

The stress-control pathway, more technically known as the Hypothalamus-Pituitary-Adrenal (HPA) axis, determines the levels of cortisol and other stress hormones in the human body. In addition to being implicated in the types of emotional and psychological stress that can lead to major depression, disorders of the stress-control pathway are also associated with obesity, premenstrual syndrome, postpartum depression, Cushing’s syndrome (hypercortisolism) and diseases including epilepsy and osteoporosis.

“We have identified a novel mechanism regulating the body’s response to stress by determining that neurosteroids are required to mount the physiological response to stress. Moreover, we were able to completely block the physiological response to stress as well as prevent stress-induced anxiety,” said author Jamie Maguire, PhD, assistant professor in the department of neuroscience at Tufts University School of Medicine and a member of the Neuroscience and Pharmacology & Experimental Therapeutics program faculties at the Sackler School of Graduate Biomedical Sciences at Tufts.

Using the brain tissues of adult mice, the research team identified mechanisms controlling the activity of Corticotrophin Releasing Hormone (CRH) neurons involved in the control of the stress pathway. By monitoring the activity of CRH neurons following stress and measuring levels of corticosterone in the blood, they found that the production of stress hormones required the action of neurosteroids on specific receptors on CRH neurons.

Apart from the finding that stress causes a neurosteroid-induced increase in blood corticosterone levels, the researchers also found that blocking the synthesis of neurosteroids is sufficient to block the stress-induced elevations in corticosterone and prevent stress-induced, anxiety-like behavior in mice. Previous research had identified the presence of specialized CRH-nerve-cell receptors in the HPA axis, but the findings had been controversial because of limited studies showing any connection between these receptors and the regulation of the CRH nerve cells.

“We have found a definite role of neurosteroids on the receptors regulating CRH nerve cells and the stress response. The data suggest that these receptors may be novel targets for control of the stress-control pathway. Our next work will focus on modulating these receptors to treat disorders associated with stress, including epilepsy and depression-like behaviors,” said Maguire.

The first author on the study is Jhimly Sarkar, PhD, formerly a postdoctoral associate in the neuroscience department at TUSM. Additional authors are Seth Wakefield, BS, a neuroscience graduate student at the Sackler School; Georgina MacKenzie, PhD, a postdoctoral associate in neuroscience at TUSM; and Stephen Moss, PhD, professor of neuroscience at TUSM and a member of the neuroscience program faculty at the Sackler School.

This study was supported by grants from the American Federation for Aging Research and the National Institute of Neurological Disorders and Stroke (NINDS), part of the National Institutes of Health.

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Sackler Team Explores Cadherin Loss in Cancer Development

Tue, 01 Nov 2011 00:00:00 -0400

Boston (November 1, 2011)

A study has uncovered a new link between development of a common type of cancer, squamous cell carcinoma (SCC), and low activity of E-cadherin protein, which keeps cells bound together in healthy tissue. In a paper published in the Journal of Investigative Dermatology, a cross-disciplinary team of researchers from Tufts University report that the loss of E-cadherin in SCC tumor cells resulted in elevated activity of two specific regulatory proteins that further lead to E-cadherin loss. This loop contributes to cancer development. These regulatory proteins could be novel targets for drug therapy in SCC.

“One of the hallmarks of SCC is the loss of the “glue” – the E-cadherin protein – between cancerous cells. The loss of this protein is one of the steps that precedes the development of cancer,” said first author Addy Alt-Holland, PhD, MSc, assistant professor of endodontics at Tufts University School of Dental Medicine (TUSDM). She also works with Jonathan Garlick in the division of cancer biology and tissue engineering at TUSDM.

For their study, the researchers generated three-dimensional engineered tissues from human skin cells that had decreased E-cadherin (control) or simultaneously decreased E-cadherin and either of the two regulatory proteins (experimental). Surface transplantation of the control tissues to mice resulted in the development of aggressive SCC, while transplantation of the experimental tissues resulted in low-grade benign skin tumors.

“Our results show that controlling the activity of either of these two regulatory proteins, FAK and Src kinases, can prevent the loss of E-cadherin and re-establish the glue between cells, pre-empting the development of aggressive cancer. Thus, our results could help in the development of new treatments for skin and similar cancers, such as oral cancers,” said Alt-Holland.

“This study furthers our understanding in the molecular events that regulate the early events in SCC development,” said senior author Jonathan Garlick, DDS, PhD, head of the division of cancer biology and tissue engineering at Tufts University School of Dental Medicine. “Our three-dimensional tissues are a biologically-meaningful system to study cancer development as it occurs in humans, and this research demonstrates their clinical relevance.”

Garlick is also a professor of oral and maxillofacial pathology at TUSDM, a member of the cell, molecular & developmental biology program faculty at the Sackler School of Graduate Biomedical Sciences at Tufts, and director of the Center for Integrated Tissue Engineering at TUSDM, which is dedicated to furthering the understanding of regenerative medicine through the investigation of three-dimensional tissue models.

According to the National Cancer Institute, skin cancers are the most common type of cancer in the United States, and SCC is the second most common type of skin cancer. It represents 15% of skin cancers, most often occurring in the head and neck. Prolonged, exposure, usually over years, to harmful sun rays, smoke, and industrial chemicals could lead to development of this disease.

Additional authors on the study are Adam Sowalsky, PhD, a graduate of the Sackler School of Graduate Biomedical Sciences, now a research fellow at Beth Israel Deaconess Medical Center; Yonit Szwec-Levin, DMD, assistant professor in the department of endodontics, TUSDM; Yulia Shamis and Harold Hatch, both PhD students at the Sackler School; and Larry Feig, PhD, professor in the department of biochemistry at Tufts University School of Medicine and member of both the biochemistry and neuroscience program faculties at the Sackler School.

This study was published in the November 2011 issue of the Journal of Investigative Dermatology and supported by grants from the National Institute of Dental and Craniofacial Research (DE011250 and DE017413), and the National Institute of General Medical Sciences (GM047717), both of the National Institutes of Health.

Alt-Holland A, Sowalsky A, Szwec - Levin Y, Shamis Y, Hatch H, Feig L, Garlick J. 2011. Suppression of E-cadherin function drives the early stages of Ras – induced squamous cell carcinoma through up-regulation of FAK and Src. J Invest Dermatol. 131: 2306–2315.

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If you are a member of the media interested in learning more about this topic, or speaking with a faculty member at the Tufts University School of Dental Medicine or another Tufts health sciences researcher, please contact Siobhan Gallagher at 617-636-6586.

Tufts Team Attacks Breast Cancer

Mon, 31 Oct 2011 00:00:00 -0400

Boston and Medford/Somerville (October 31, 2011)

A team of scientists at Tufts University will develop ultra-sensitive techniques at the single-molecule and single-cell levels designed to detect breast cancer earlier, and treat it with greater precision, through a $6.6 million Innovator Award from the Department of Defense Breast Cancer Research Program made to Tufts chemist David R. Walt, PhD.

The Innovator Awards provide "individuals who have a history of creativity, innovative work, and leadership with the funding and freedom to pursue their most novel, visionary, high-risk ideas that could ultimately lead to the eradication of breast cancer."

Principal Investigator Walt, who is Robinson Professor of Chemistry at Tufts' School of Arts and Sciences and a Howard Hughes Medical Institute Professor, applies micro- and nanotechnology to urgent biological problems. Technologies that have come out of his laboratory include DNA microarrays, sequencing methods, medical diagnostic methods, and basic biochemistry research. He is credited with the first documented use of the word "microarray" in the scientific literature.

Collaborating with Walt are three Tufts specialists in breast cancer: Rachel Buchsbaum, MD, the Diane Connolly-Zaniboni Scholar in Breast Cancer Research in the Molecular Oncology Research Institute at Tufts Medical Center, associate professor at Tufts University School of Medicine, and a breast oncologist and researcher on molecular mechanisms of metastasis and the cancer microenvironment; Charlotte Kuperwasser, PhD, associate professor at Tufts University School of Medicine and an expert on stem cell and tissue regulation of the molecular pathways of breast cancer progression; and Gail Sonenshein, PhD, professor at Tufts University School of Medicine, internationally known for her work in molecular signaling mechanisms in breast cancer. Buchsbaum, Kuperwasser and Sonenshein are also program faculty at the Sackler School of Graduate Biomedical Sciences at Tufts.

In addition, University of Washington chemist Daniel T. Chiu, PhD, a leader in microfluidics, will collaborate with the team.

"While great progress has been made in early breast cancer detection and treatment, current methods cannot always determine if a tumor has metastasized or accurately characterize its cellular diversity. Nor do we understand how to distinguish those early breast cancers that are potentially lethal from breast cancers that are unlikely to recur or spread after initial treatment," said Buchsbaum.

The research team will use Walt’s single-molecule techniques to uncover new biomarkers in the blood that they hope will have the specificity needed to accurately screen for breast cancer and to diagnose and predict the outcome of breast cancer. They will also characterize breast cancer biopsy samples with single-cell resolution to discover the nature of these complex cell populations so that more precise therapies can be devised.

"Our hope is to detect cancer-relevant biomarkers that would enable breast cancer screening to convert from mammography to a simple blood test," said Walt. "Identification of such biomarkers would represent a major clinical advance."

"By developing more sensitive and biologically precise tools for detecting breast cancer, patients can be diagnosed earlier in the disease process and the tumors better characterized. We hope this research will translate to more targeted therapeutic approaches, with higher efficacy and fewer side effects," said Sonenshein.

Tufts University, located on three Massachusetts campuses in Boston, Medford/Somerville and Grafton, and in Talloires, France, is recognized among the premier research universities in the United States. Tufts enjoys a global reputation for academic excellence and for the preparation of students as leaders in a wide range of professions. A growing number of innovative teaching and research initiatives span all campuses, and collaboration among the faculty and students in the undergraduate, graduate and professional programs across the university is widely encouraged.

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For more information on this news release, please contact Kim Thurler at 617.627.3175.

Sackler Investigators Identify Gene Associated with Bipolar Disorder

Tue, 25 Oct 2011 00:00:00 -0400

BOSTON (October 25, 2011)

Low levels of a brain protein that regulates gene expression may play a role in the origin of bipolar disorder, a complex and sometimes disabling psychiatric disease. As reported in the latest issue of Bipolar Disorders, the journal of The International Society for Bipolar Disorders, levels of SP4 (specificity protein 4) were lower in two specific regions of the brain in postmortem samples from patients with bipolar disorder. The study suggests that normalization of SP4 levels could be a relevant pharmacological strategy for the treatment of mood disorders.

“We found that levels of SP4 protein in the brain’s prefrontal cortex and the cerebellum were lower in postmortem samples from patients with bipolar disorder, compared with samples from control subjects who did not have the disease,” said co-senior author Grace Gill, PhD, an associate professor in the department of anatomy and cellular biology at Tufts University School of Medicine and a member of the neuroscience; genetics; and cell, molecular and developmental biology program faculties at the Sackler School of Graduate Biomedical Sciences at Tufts.

Gill’s laboratory team at Tufts collaborated with researchers from Spain and used postmortem samples from Spain’s University of the Basque Country brain collection program to examine SP4 protein levels in samples from 10 bipolar subjects and 10 control subjects matched for gender, age, and time since death.

The team focused on the prefrontal cortex and the cerebellum because brain imaging studies suggest that bipolar disorder is associated with changes in the structure of these brain regions. Little is known about the cellular and molecular changes that occur in bipolar disorder, especially in the cerebellum.

“Our findings suggest that reduced activity of the SP4 protein may be common in bipolar disorder,” stated co-senior author Belén Ramos, PhD, a former postdoctoral fellow in Gill’s lab and now a researcher at the Parc Sanitari Sant Joan de Déu (PSSJD) and the Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM) in Barcelona, Spain.

Ramos explained that SP4 belongs to a category of proteins known as transcription factors, which regulate gene expression. “While this study examined the SP4 protein levels, mutations in the gene encoding the SP4 protein have been associated with psychiatric diseases including bipolar disorder, a poorly understood disease characterized by episodes of abnormally elevated energy levels with or without depressive episodes, as well as schizophrenia, and major depressive disorder. Thus, our study adds to the growing body of evidence that alterations in gene regulation contribute to the development of psychiatric disorders,” said Ramos.

Further analysis showed that SP4 levels are regulated by neuronal activity, indicating that this transcription factor is important for normal neuronal signaling. “Looking at normal rat neurons in culture, we found that SP4 is rapidly degraded by enzymes in the absence of neuronal signaling, which we refer to as the non-depolarized state,” said first author Raquel Pinacho, BS, MS, a graduate student in Ramos’ lab in PSSJD.

In previous work, the researchers had identified an essential role for SP4 in regulating the structure of nerve cells during development. Taken together, the findings suggest that reduced levels of this protein may contribute to altered patterns of nerve cells in the brain.

“Moreover,” added Ramos, “we demonstrated that the destruction of SP4 by enzymes was inhibited by lithium, a drug widely used as a mood stabilizer for patients with bipolar disorder. When lithium was added to cells in the non-depolarized -- inactive -- state, levels of SP4 were stabilized and increased. This finding suggests that the therapeutic effects of lithium may be related, at least in part, to changes in gene expression leading to changes in cellular structure and function.”

In addition to measuring levels of SP4, Gill and colleagues assessed levels of SP1, a related transcription factor protein that has been reported to be altered in schizophrenia. Like SP4, SP1 was reduced in the cerebellum of subjects with bipolar disorder. According to the authors, this finding suggests that both factors may be relevant transcriptional regulators, low levels of which may contribute to the pathogenesis of bipolar disorder and other psychiatric diseases. However, unlike SP4, levels of SP1 did not appear to be regulated by neuronal activity, highlighting the complexity of the mechanisms involved in functional specificity in the SP transcription factor family.

Additional authors on the study are Nuria Villalmanzo, a research assistant in Ramos’s lab in PSSJD, Jasmin Lalonde, PhD, a postdoctoral fellow in Gill’s lab at TUSM; Josep Maria Haro, MD, PhD, of PSSJD and CIBERSAM; and J. Javier Meana, MD, PhD, professor in the department of pharmacology at the University of the Basque Country in Bizkaia, Spain, and CIBERSAM.

The study was funded by the National Institute of Child Health and Human Development, part of the National Institutes of Health, a Marie Curie International Reintegration Grant (European Union) and the Plan National de Investigación (Spain). This study was also supported by fellowships to authors from the Spanish Ministry of Science and Education /Fulbright, CIBERSAM, and from the Canadian Institutes of Health Research.

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Moss Partners with Harvard Team to Reveal Insights into Memory

Thu, 22 Sep 2011 20:56:00 -0400

Sackler Team Probes Origin of Rare Form of Breast Cancer

Thu, 22 Sep 2011 20:35:00 -0400

BOSTON (September 22, 2011)

Identifying the cellular origins of breast cancer might lead to earlier diagnosis and more efficient management of the disease. New research led by Charlotte Kuperwasser of Tufts University School of Medicine (TUSM) has determined that common forms of breast cancer originate from breast cells known as luminal epithelial cells while rarer forms of breast cancer, such as metaplastic carcinomas, originate from basal epithelial cell types. The study was published ahead of print this week in PNAS Early Edition as part of its breast cancer special feature.

Clinicians and researchers classify breast cancers into subtypes based on both clinical features and molecular features, including expression of certain genes and proteins. These classifications help determine diagnosis, treatment decisions, and patient prognosis. The most common form of breast cancer, called invasive ductal carcinoma, is classified broadly into two types based on molecular features of the tumor cells: luminal-like cancers, which are sensitive to hormones, and the more aggressive basal-like cancers, which are not sensitive to hormones and tend to have a poorer prognosis.

However, there are also rare forms of breast cancer, some of which are called metaplastic carcinomas, where the cancer cells no longer resemble cells of the breast. Scientists do not yet fully understand how and why these different types of breast cancers form but one theory is that they originate from adult breast tissue stem cells.

“For the past several decades, most research efforts have been focused on discovering cancer-causing genes in hope that this information might help us discover better treatments for breast cancer. While these efforts have led to successes in treating some common forms of breast cancer, they have not provided us with information regarding where breast cancer originates and in particular, the origins of rare forms of metaplastic breast cancers for which the best course of treatment has not yet been determined,” said Kuperwasser, PhD, associate professor in the department of anatomy and cellular biology, Tufts University School of Medicine, and a member of the genetics and cell, molecular & developmental program faculties at the Sackler School of Graduate Biomedical Sciences at Tufts and the Molecular Oncology Research Institute (MORI) at Tufts Medical Center.

In light of this, the research team chose to study the two major types of cells in the human breast, those that line the ducts and produce milk (luminal cells) and those that surround the ductal cells and contract to move the milk from the ducts (basal/myoepithelial cells) to determine whether they might form different types of breast cancers.

“We found that when basal/myoepithelial breast cells become cancerous they no longer resemble breast tissue; instead they look more like cells of the skin and form rare metaplastic breast cancers. In contrast, when luminal breast cells become cancerous, they retain the structure and molecular features of more common types of breast cancers,” said first author Patricia Keller, PhD, post-doctoral associate in the anatomy and cellular biology department at TUSM and a member of the Kuperwasser lab and MORI.

The researchers introduced cancer-causing genes into healthy breast cells obtained from breast reduction surgeries. Using specialized markers, they were able to isolate different types of normal breast cells and evaluate how they behaved as they became cancerous in a mouse model.

“By understanding more about the cellular beginnings of cancer, we can direct our research toward investigating preventive methods and possibly even developing new therapies,” said Kuperwasser.

This study adds to Kuperwasser’s growing body of work in breast cancer research. Earlier work identified a mechanism behind the preferential formation of aggressive breast cancers in people carrying a mutated BRCA1 gene. A team co-led by Kuperwasser and Philip Hinds, of Tufts Medical Center, also proposed and supported a model for breast cell differentiation that identified two distinct populations of progenitor cells for breast cancer. Her work has been published in Cell Stem Cell, Breast Cancer Research, Cancer Cell, and Nature Protocols.

Additional authors on the study are Lisa Arendt, PhD, DVM, senior research associate in the Kuperwasser lab at TUSM and Tufts Medical Center; Adam Skibinski, an MD, PhD student in the cell, molecular and development biology program at the Sackler School of Graduate Biomedical Sciences at Tufts; Tanya Logvinenko, PhD, of the Biostatistics Research Center, Institute for Clinical Research and Health Policy Studies, Tufts Medical Center; Shumin Dong, MD, formerly of the department of oral and maxillofacial pathology at Tufts University School of Dental Medicine; Ina Klebba, BSc, formerly a senior research assistant in Kuperwasser’s lab; Avi E. Smith, BA, research technician at Tufts University School of Dental Medicine; Aleix Prat, MD, and Charles Perou, PhD, both of the departments of genetics, and pathology & laboratory medicine, Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill; Hannah Gilmore, MD, and Stuart Schnitt, MD, both of the departments of pathology and medicine, Beth Israel Deaconess Medical Center and Harvard Medical School; Stephen Naber, MD, PhD, of the department of pathology, Tufts Medical Center, and Jonathan A. Garlick, DDS, PhD, of the division of cancer biology & tissue engineering as well as the department of oral and maxillofacial pathology, Tufts University School of Dental Medicine.

This work was supported by a Broadway on Beachside Postdoctoral Fellowship from the New England Division of the American Cancer Society; and by grants from the Raymond and Beverly Sackler Foundation, the Breast Cancer Research Foundation, the Department of Defense Breast Cancer Research Program; and the National Cancer Institute and the National Institute of Dental & Craniofacial Research, both of the National Institutes of Health.

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Sackler Team Develops Promising Therapy for AMD

Fri, 29 Apr 2011 00:00:00 -0400

Boston (April 29, 2011)

A gene therapy approach using a protein called CD59, or protectin, shows promise in slowing the signs of age-related macular degeneration (AMD), according to a new in vivo study by researchers at Tufts University School of Medicine. Led by senior author Rajendra Kumar-Singh, PhD, the researchers demonstrated for the first time that CD59 delivered by a gene therapy approach significantly reduced the uncontrolled blood vessel growth and cell death typical of AMD, the most common cause of blindness in the elderly. The study was published on April 28 in PLoS ONE.

Activation of the complement system, a part of the immune system, is responsible for slowly killing cells in the back of the eye, leading to AMD. Activation of this system leads to the generation of pores or holes known as ‘membrane attack complex’ or MAC in cell membranes. CD59 is known to block the formation of MAC.

“CD59 is unstable and hence previous studies using CD59 have had limited success. The gene therapy approach that we developed continuously produces CD59 in the eye and overcomes these barriers, giving us renewed hope that it can be used to fight the progression of AMD and potentially other diseases,” said Kumar-Singh.

Kumar-Singh is associate professor in the department of ophthalmology at Tufts University School of Medicine (TUSM) and member of the genetics; neuroscience; and cell, molecular, and developmental biology program faculties at the Sackler School of Graduate Biomedical Sciences at Tufts.

Kumar-Singh and colleagues delivered CD59 to the eye using a deactivated virus similar to one previously shown to be safe in humans. Using an established mouse model of age-related macular degeneration, they found that eyes treated with CD59 had 62 percent less uncontrolled blood vessel growth and 52 percent less MAC than controls.

“Treatment was effective when administered at a very specific location beneath the retina, but importantly, also when it was administered to the center of the eye. This finding is especially encouraging because it would allow for a safer and more convenient route of administration of treatment,” said co-first author Siobhan Cashman, PhD, assistant professor in the department of ophthalmology at Tufts University School of Medicine and member of Kumar-Singh’s lab.

The current standard treatment for some forms of AMD requires an injection directly into the eye approximately every four weeks. According to Kumar-Singh, gene therapy approaches to treat AMD are especially attractive because they will allow patients to be treated less frequently, reducing patient discomfort and lowering chances of infection and other side effects associated with frequent injections into the eye.

The researchers, including co-first author Kasmir Ramo, BS, research technician, believe that while CD59 has significant potential as a treatment for AMD, the gene therapy approach lends itself for application also in other eye and systemic disorders where low-level activation of complement has been implicated.

“Prior to initiating human clinical trials, we will need to perform extensive preclinical toxicology studies. In order to advance this study to Phase I clinical trials, we have formed a partnership with Hemera Biosciences Inc. to raise private venture capital,” said Kumar-Singh.

AMD, which results in a loss of sharp, central vision, is the number one cause of visual impairment among Americans age 60 and older. While treatments are available for wet AMD, they do not prevent the progression of dry AMD, the form that affects 90 percent of AMD patients. Kumar-Singh noted, however, that the current study in combination with a previously published study from his laboratory suggests that CD59 may be useful for the treatment of both the dry and wet forms of AMD.

This study was supported by grants from The Ellison Foundation; the National Eye Institute, part of the National Institutes of Health; the Virginia B. Smith Trust and grants to the department of ophthalmology at TUSM from the Lions Eye Foundation and Research to Prevent Blindness.

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Promising HPV Therapeutic Under Development at Sackler

Tue, 26 Apr 2011 00:00:00 -0400

Boston (April 26, 2011)

Human papillomavirus (HPV) causes cervical cancer, the second most common cause of cancer death for women, and is a common cause of anogenital and some head and neck cancers. Thanks to research being done at Tufts University School of Medicine, patients infected with cancer-causing HPV may someday have an alternative to surgical and harsh chemical treatments. In a study funded by the National Institutes of Health and published online in advance of print in The FASEB Journal, the researchers report on the development of a protein-based inhibitor that could provide a topical treatment for HPV.

“Currently, there is no cure for HPV, and the available treatment options involve destroying the affected tissue. We have developed a protein inhibitor that blocks HPV protein expression in cell culture, a first step toward a topically-applied treatment for this cancer-causing virus,” said senior author James Baleja, PhD, associate professor of biochemistry at Tufts University School of Medicine (TUSM) and member of the biochemistry program faculty at the Sackler School of Graduate Biomedical Sciences at Tufts.

“Vaccines are helping to lower the incidence of HPV, but vaccines will not help the millions of women and men who currently have an infection, especially those who have high-risk and persistent infections. Social and economic challenges make widespread administration of a vaccine difficult, particularly in developing countries. A topical treatment for HPV could provide an economical option,” he continued.

HPV affects approximately 20 million people in the United States, making it the most common sexually transmitted infection. There are more than 100 types of HPV of which more than 40 are sexually transmitted. These include two high-risk types, HPV-16 and HPV-18, which cause the majority of cervical and anogenital cancers, and some portion of head and neck cancers, particularly oral cavity and oropharynx cancers. Cervical cancer is diagnosed in nearly 500,000 women each year, killing 250,000 annually. In the United States, it was estimated that 12,000 women in 2010 would be diagnosed with cervical cancer, while 10,100 women and men in the United States get vulvar, vaginal, penile or anal cancers each year. In addition, some portion of the head and neck cancers in the United States (11,300 men and women each year) is attributable to HPV. Other types of HPV, or low-risk HPV, can cause genital warts or are infections that clear on their own.

In their efforts to inhibit HPV, Baleja and his team zeroed in on the viral protein E2, which controls viral activities including DNA replication and the activation of cancer-causing genes. Using structure-guided design, the team developed a protein called E2R that prevents E2 from functioning normally. When the researchers applied E2R to a cell model of HPV biology, viral gene transcription was halted. Because HPV infects epithelial cells, the outermost layer of the skin and the mucous membranes, protein inhibitors such as E2R could be applied in a topical form.

Baleja and colleagues used biophysical tools including circular dichroism spectroscopy and x-ray crystallography to test the structure and stability of different inhibitors. The most stable inhibitor was then tested in mammalian cells and was found to inhibit the E2 protein of HPV-16, the high-risk strain that is most commonly associated with cancers. The data in this study suggest that the inhibitor may also be effective against another high-risk virus, HPV-18, as well as a low-risk virus, HPV-6a, which causes warts.

Additional authors on the paper are first author Kakoli Bose, PhD, formerly a post doctoral fellow in the Baleja laboratory at TUSM and now with the Advanced Centre for Treatment, Research and Education in Cancer at the Tata Memorial Center in India; Gretchen Meinke, PhD, senior research associate in the Bohm Laboratory at TUSM, and Andrew Bohm, associate professor in the Department of Biochemistry at TUSM and member of the biochemistry program faculty at the Sackler School of Graduate Biomedical Sciences.

This research was funded by the National Cancer Institute, part of the National Institutes of Health, and by the Lifespan/Tufts/Brown Center for AIDS Research (CFAR), a joint research effort between Tufts and Brown Universities and their affiliated hospitals and centers. CFAR is funded by the National Institute of Allergy and Infectious Diseases, part of the National Institutes of Health.

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Sackler Student and Mentor Identify Gene-Diet Links to Obesity

Wed, 20 Apr 2011 00:00:00 -0400

Boston (April 20, 2011)

Eating more n-3 polyunsaturated fatty acids, commonly known as omega-3 fatty acids, may help carriers of a genetic variant on the perilipin 4 (PLIN4) gene locus lose weight more efficiently. Based on this observation, researchers at the Jean Mayer Human Nutrition Research Center on Aging (USDA HNRCA) at Tufts University identified a microRNA (miRNA) which may elucidate the underlying biological mechanism.

Led by Jose M. Ordovas, PhD, director of the Nutrition and Genomics Laboratory at the USDA HNRCA, researchers genotyped seven single nucleotide polymorphisms (SNPs), also known as gene variants, from men and women of mostly white European ancestry enrolled in the Genetics of Lipid Lowering Drugs and Diet Network (GOLDN) study and the Framingham Offspring Study. Carriers of the gene variant tended to weigh more and exhibit higher body mass index (BMI), which would increase their risk of becoming obese. Yet carriers with higher omega-3 fatty acid intakes tended to weigh less than carriers who consumed little or no omega-3 fatty acids.

Ordovas believes this to be the first example of a genetic variant that creates a miRNA binding site that influences obesity-related traits through a gene-diet interaction. Although further research is necessary, the findings suggest that miRNA activity is a possible target for dietary-based weight-loss therapies for obesity. The results were published online April 20 by the journal PLoS ONE.

"We tested for miRNA activity after seeing significant interactions between the gene variant, characteristics of obesity, and omega-3 fatty acid intake in our meta-analysis in two large populations," says Ordovas, who is also a professor at the Friedman School of Nutrition and Science Policy at Tufts and a member of the genetics graduate program at the Sackler School of Graduate Biomedical Sciences. "When a gene variant is that informative, you get a strong sense that it may be functional."

The family of perilipin genes controls the release of perilipin proteins which dictate how fat is stored and broken down in the body. The current study adds to a body of research of the perilipin gene family and its role in obesity risk, yet most of the work focuses on perilipin 1 (PLIN1). "In the past, studies have shown gene variants in the PLIN1 gene locus are associated with obesity risk and appear to be regulated by polyunsaturated fat. It is encouraging that we saw both loci expressed in similar ways," Ordovas adds.

Ordovas and colleagues say future studies could explore the role of miRNA in both the PLIN1 and PLIN4 genes. "Variants that may create or destroy miRNA binding sites have tremendous potential for functional consequence, and we would want to investigate if this is occurring in the other perilipin genes," says Kris Richardson, MS, corresponding author and a doctoral student at the Sackler School of Graduate Biomedical Sciences at Tufts. "Also, replication of our results in larger populations which record the dietary information of its participants would help clarify the role of perilipin genes interacting with dietary fats such as omega-3 fatty acids and impacting weight."

Omega-3 fatty acids are polyunsaturated fats mostly found in fatty fish such as tuna, salmon and sardines. The recently-issued 2010 Dietary Guidelines for Americans say that "(f)at intake should emphasize monounsaturated and polyunsaturated fats."

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If you are a member of the media interested in learning more about this topic, or speaking with a faculty member at the Friedman School of Nutrition Science and Policy at Tufts University, the Sackler School of Graduate Biomedical Sciences or another Tufts health sciences researcher, please contact Andrea Grossman at 617-636-3728, Christine Fennelly at 617-636-3707 or Siobhan Gallagher at 617-636-6586.

Molecular Microbiology Alum Testifies Before Senate Subcommittee

Thu, 07 Apr 2011 00:00:00 -0400

Tufts Receives Patent for Antibody Treatment against Hemolytic Uremic Syndrome

Fri, 25 Feb 2011 00:00:00 -0500

GRAFTON, MA (February 25, 2011)

Researchers at the Cummings School of Veterinary Medicine have received U.S. patent approval for an antibody-based treatment for Hemolytic Uremic Syndrome (HUS), a potentially fatal outcome of E. coli poisoning and the leading cause of kidney failure in children.

HUS is caused by the forms of E. coli that produce Shiga toxins and are responsible for about 100,000 annual cases of illness in the United States alone. Typically, individuals will develop bloody diarrhea and recover—however, 5-15 percent of children, the elderly and individuals whose immune systems are compromised may develop HUS in addition after several days.

The condition causes kidney damage and can lead to chronic, irreversible kidney dysfunction, which can be fatal. HUS can also cause damage to the central nervous system. There is currently no cure for the condition.

The condition is believed to be caused by one of the two types of Shiga toxin excreted by E. coli, known as Stx2 and Stx1. The Tufts approach to treating HUS, led by Dr. Saul Tzipori, director of the Cummings School’s Division of Infectious Diseases, utilizes human monoclonal antibodies that seek out and bind to the Stx and, ultimately, neutralize it. In a 2004 study, Dr. Tzipori was able to show its efficacy both in vitro and in vivo using mice and pig models.

Other attempts to neutralize Stx have been attempted using other types of antibodies—chimeric and humanized—where mouse antibodies are fused with parts of human antibodies. However, Tzipori and his colleagues utilized antibodies from transgenic mice specially bred to express human antibodies—creating a safer, longer-lasting, and more effective treatment, Tzipori says.

“In addition to the other benefits, utilizing this approach of generating human antibodies enabled us to create a large number of them from which to select,” said Distinguished Professor of Microbiology and Infectious Diseases Dr. Saul Tzipori.

The patent is currently licensed to Sarasota, Fla.-based Lakewood-Amedex Inc.

The Division of Infectious Diseases at the Cummings School of Veterinary Medicine is Tufts University’s largest research division. The division also oversees the New England Regional Biosafety Laboratory, a 41,000 square foot, level-2 and level-3 facility dedicated to the study of existing and emerging infectious, diseases, toxin-mediated diseases and medical countermeasures important to biodefense.

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For more information on this news release, please contact Tom Keppeler at tom.keppeler@tufts.edu

Tufts Institute for Biopharmaceutical Partnerships Launches New Hub

Wed, 09 Feb 2011 00:00:00 -0500

BOSTON, MA (February 7, 2011)

Tufts University today announced the public launch of the Tufts Institute for Biomedical Partnerships website/HUB: www.tuftspharmapartners.org

The Institute is university-wide, global pharmaceutical partnering initiative designed to create and manage a diverse portfolio of drug discovery and development partnerships.

The Institute was developed and is managed by Tufts University School of Medicine and Tufts University’s Advancement Division.

“Our objective is to form innovative drug discovery and development alliances between Tufts and the pharma industry based on existing assets of strategic interest, while generating revenue streams to benefit the university and industry alike. To this end, we’re focused on establishing a global brand for Tufts drug discovery and development expertise,” said Lawrence J. Botticelli, Ph.D., Founder and current Chief Business Officer of the Institute.

The Institute’s website is an interactive web medium, or “HUB”, custom-developed and designed to educate and engage pharma partners, qualify partners and create distinctive alliances. The website functions as the Institute's principal commercialization portal, communication vehicle, strategic market resource, and information repository. It is designed to facilitate a distinctive approach to raising industry knowledge and awareness of Tufts' established expertise and the formation of important strategic alliances. Current information in the HUB includes five thematic areas of expertise derived from five different schools and one center. The site provides immediate access to nearly 60 research activities driven by more than 50 participating faculty members with navigable information in more than 300 categories.

“The creation of the HUB and the Tufts Institute for Biopharmaceutical Partnerships represents a landmark event and presents an exciting opportunity to those of us engaged in the discovery and innovation process,” said Ira Herman, Ph.D., Professor and Director of the Program in Cellular and Molecular Physiology, Center for Innovations in Wound Healing Research at Tufts University School of Medicine. “We hope that this new portal will enable us to establish meaningful partnerships focused on delivering novel therapeutics and cutting edge technologies, as well as significantly extend current standards of care and clinical practice, locally and globally.”

In his recent review of the website/HUB, David Damassa, Ph.D., Dean, Information Technology, Tufts University School of Medicine, commented, “The recently-published Institute for Biopharmaceutical Partnerships website, with its innovative Global Pharma Strategy & Project Development HUB, is a wonderful new resource benefitting both the global pharmaceutical industry and Tufts University. The design of the site and its theme areas of “Discover | Collaborate | Innovate” truly capture the unique culture of Tufts University… Particularly compelling are the advanced search features of the HUB and its ability to create individual profiles so that use can be proactively connected with research and people of interest. The new site will undoubtedly raise industry knowledge and awareness of Tufts’ established expertise and ability to form strategic alliances with industry, resulting in the development of important new drugs and technologies.”

The Institute website/HUB introduces the pharma industry to a range of thematic areas of drug discovery and development expertise:

Innovative Therapies (Cancer, Infectious Disease, Cardiometabolic and Pulmonary Disorders, Neurological and Psychiatric Disorders),
Technology Platforms (Biomaterials and Biological scaffolding, Genetics, Genomics and Cell Function, Translational and Clinical Pharmacology, Functional Tissue Engineering, Functional Proteomic Screens),
Discovery & Development Services (Target Identification and Validation, Structural and Chemical Biology-Based Drug Design, Metabolic Analysis of Drug Candidates, In Vitro Models of Drug Transport, Experimental and Spontaneous Models of Disease),
Drug Development Science (Drug Disposition and Clinical Pharmacokinetics, Clinical Pharmacology, Drug Development and Regulation, Protocol Design and Complexity, New Models of Pharmaceutical Innovation, Pharmaceutical Economics)
Research Constellations (Establishment of non-traditional networks of robust research activities, including Regenerative Medicine, Biology and Aging, and Inflammation).

“The website/HUB is not simply an electronic repository of individuals, but a cogent, strategic expression of potential commercialization opportunities,” said Dr Botticelli.

Researchers and companies interested in learning more about the University’s drug discovery and development capabilities and how best to enter into a collaborative relationship with Tufts, can access information by navigating through the introductory “Institute” overview and learn about the Institute’s focus, leadership, business model, and research, technology, and science, as well as research constellations that it represents. Upon entering the “HUB,” users can obtain relevant information regarding therapeutic areas, technology platforms, discovery and development services, drug development science, and robust non-traditional research networks, including specific Tufts University practitioners engaged in such activities. Under “Faculty Member Profiles” detailed information on principal investigators can be obtained, including biosketches, areas of research interest, intellectual property estates, industry experiences, and relevant scientific publications.

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Sonenshein Elected AAAS Fellow

Fri, 14 Jan 2011 17:31:00 -0500

BOSTON (January 14, 2011) —Abraham L. (Linc) Sonenshein, PhD, professor of molecular biology and microbiology at Tufts University School of Medicine and member of the genetics and molecular microbiology program faculties at the Sackler School of Graduate Biomedical Sciences at Tufts has been awarded the distinction of AAAS Fellow.

Election as a Fellow is an honor bestowed upon AAAS members by their peers. Fellows are awarded because of their scientifically or socially distinguished efforts to advance science or its applications. Sonenshein was elected for his distinguished contributions to the understanding of gene regulation, sporulation and pathogenesis in Gram-positive bacteria.

Sonenshein, who is also the acting chair of molecular biology and microbiology at Tufts School of Medicine, studies the regulation of gene transcription in the spore-forming bacteria Bacillus subtilis and Clostridium difficile, and the relationship of sporulation to pathogenesis.

His work with the “superbug,” C. difficile which causes severe diarrhea in patients and sometimes death, showed that the bacteria only produce toxins when they are limited for nutrients. Essentially, protein that monitors the nutrient levels inside C. difficile cells prevents toxin production when the bacteria have enough to eat.

This and his other work with C. difficile are important steps toward the development of a drug that may prevent hospital patients from falling ill.

In ongoing work, he is collaborating with scientists at the Cummings School of Veterinary Medicine at Tufts and Boston University to use the harmless B. subtilis bacterium as the basis for low-cost, needle-free and heat-stable vaccines. In a study published in the November 2010 issue of Clinical and Vaccine Immunology, one such vaccine – using nasal drops instead of needles – effectively induced an immune response in mice and protected them from rotavirus infection. Rotavirus is a common cause of severe diarrheal disease that is responsible for approximately 500,000 deaths among children in the developing world every year.

The new vaccine delivery system has also been tested successfully against tetanus. A study published in Vaccine in September 2010 established that the tetanus vaccine is effective even after being stored for more than a year at 113ºF. The new vaccine delivery system is currently being tested with diphtheria and pertussis.

The American Association for the Advancement of Science (AAAS) is the world’s largest general scientific society, and publisher of the journal, Science and other leading journals. AAAS was founded in 1848, and includes 262 affiliated societies and academies of science, serving 10 million individuals. The non-profit AAAS is open to all and fulfills its mission to “advance science and serve society” through initiatives in science policy, international programs, science education, and more.

The 2010 AAAS Fellows will be recognized during the 2011 AAAS Annual Meeting in Washington, DC, in February.

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If you are a member of the media interested in learning more about this topic, or speaking with a faculty member at the Tufts University School of Medicine or the Sackler School of Graduate Biomedical Sciences, please contact Siobhan Gallagher at 617-636-6586.

JAX - Sackler Collaboration Highlighted

Wed, 05 Jan 2011 00:00:00 -0500

BAR HARBOR, MAINE and BOSTON (January 5, 2011)

The Jackson Laboratory (JAX), Sackler School of Graduate Biomedical Sciences at Tufts, and Tufts University School of Medicine have unveiled a new mammalian genetics track for PhD students. The joint track offers students in-depth research and training at both JAX and Tufts. Combining the faculty and resources of the genetics program at Tufts, with its emphasis on human disease, and the faculty and resources at JAX, with its emphasis on mouse models and bioinformatics, is expected to help address the growing international need for expertise in mammalian genetics.

The “JAX track” at Tufts provides students with the unique opportunity to conduct research rotations at both institutions and conduct their Ph.D. research at The Jackson Laboratory in Bar Harbor, Maine. Students will also continue their work in the genetics program at the Sackler School through videoconferencing and by attending retreats and other program events. In addition, students will have opportunities to engage with investigators at Tufts and Tufts Medical Center directly studying disease in patients.

According to JAX Senior Research Scientist Mary Ann Handel, Ph.D., director of the Cooperative Predoctoral Training Program, “Combining our institutional strengths with Tufts’ provides unparalleled opportunities to leverage mouse models to investigate normal human biology and disease.”

The flexible track will allow students to complete required courses and training “while taking advantage of the best of each institution,” Handel says.

“Graduate students in the new track will benefit from the resources and faculty of both institutions: the laboratory, didactic and seminar-based courses and the research laboratories working on human disease at Tufts, with the extensive mouse genetics and mouse models research laboratories at JAX,” says Erik Selsing, Ph.D, associate professor of pathology at Tufts University School of Medicine and director of the genetics graduate program at the Sackler School.

“These students in genetics also have the opportunity to attend medical genetics rounds at Tufts Medical Center and the Floating Hospital for Children, interacting with physician trainees. These experiences give students a special appreciation for the genetic diseases that affect people, ultimately helping to foster the collaborative research that will bring us closer to linking basic science research to cures for disease and the development of personalized medicine,” he continues.

Trainees begin their studies in Maine in the first week of July, prior to the start of the usual academic year. First-year research rotations will be distributed between the Boston and Maine campuses. Students will conduct their Ph.D. research at JAX, where varied biomedical research opportunities include cancer biology, genetics of complex traits, neurobiology, bioinformatics/computational biology and many other areas.

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Learn more about this program using the links below

Sackler School Genetics Program

The Jackson Laboratory Educational Programs

The JAX Track Joint PhD Program

Sackler Student and Mentor Develop New Wound Healing Strategy

Tue, 07 Dec 2010 18:05:00 -0500

BOSTON (December 7, 2010)

Newly-created bioactive peptides promote wound healing through the growth of new blood vessels and epithelial tissue, such as skin. These wound-healing peptides, synthesized by researchers at the Tufts Center for Innovations in Wound Healing Research, increased angiogenesis in vitro by 200 percent. The discovery, reported online in advance of print this week in Wound Repair and Regeneration, provides a better understanding of the mechanisms regulating wound healing and may lead to new therapies for acute and chronic wound healing.

“We identified specific bioactive peptides that are produced from collagenase treatment of extracellular matrix, which stimulate the healing process within a wound. By creating combinations of several key peptide fragments, we were able to synthesize an entirely novel class of wound-healing peptides that promote the fundamental response to injury: blood vessel formation and epithelialization,” said senior author Ira Herman, PhD, a professor of molecular physiology and pharmacology at TUSM; member of the cell, molecular & developmental biology, and cellular & molecular physiology program faculties at the Sackler School of Graduate Biomedical Sciences; and director, Tufts Center for Innovations in Wound Healing Research.

“This is the first time these peptides have been identified and synthesized and we hope that these discoveries and new technologies will have broad implications for acute, chronic, burn, and scarless wound healing,” Herman continued.

The team from Tufts used a three-dimensional wound model to examine the effect of the bioactive peptides on wound healing. After three days, wounds treated with the peptides showed signs of robust repair, while controls did not.

“We found that collagenase enzyme derived from Clostridium histolyticum bacteria releases biologically active fragments – peptides – from extracellular mammalian proteins. These peptides stimulate proliferation of capillary endothelial cells, enhance microvascular remodeling in the 2-D model, and induce endothelial sprouting in a 3-D model of injury repair, and therefore are likely to have potential to stimulate blood vessel formation and promote healing in response to injury in animals and humans,” said first author Tatiana Demidova-Rice, BS, a PhD candidate in the cell, molecular and developmental biology program at the Sackler School of Graduate Biomedical Sciences at Tufts.

Angiogenesis, the formation of new blood vessels from existing vessels, is a key step in all types of wound healing from knee scrapes to venous stasis ulcers, pressure sores and diabetic foot ulcers. In order for tissues to be repaired, there must be an adequate blood supply bringing nutrients, oxygen, and signaling molecules to the site of the injury. Collageneses are enzymes that remodel extracellular matrix by cleaving one of its key components, collagen.

“The most potent wound-healing peptide is a ‘combinatorial’ peptide synthesized from bioactive fragments derived from the collagenase treatment of biosynthesized matrix. Outcomes of these studies suggest that it could be possible to create personalized regenerative medicine-based wound healing therapies and platforms that would be tailored to individuals. We are currently testing the efficacy of these fragments in an effort to develop better treatments for wound healing. Formulation of the bioactive peptides into heat-stable and portable materials could be of extreme value to soldiers injured in combat,” said Herman.

As director of the Tufts Center for Innovations in Wound Healing Research (TIWR), Herman brings together investigators from a broad range of disciplines to advance wound healing research and therapeutics. Researchers combine recent insights and advances in wound-healing biology, materials sciences, and bioengineering to create fully-vascularized organ constructs for personalized regenerative medicine, while offering new and innovative opportunities for drug screening, discovery and development. TIWR investigators are currently developing cutting-edge technologies in biomaterials sciences and nano-fabrication processing to create personalized wound healing therapeutics, including “next generation” wound care products for civilian and soldier use.

An additional author on the study is Anita Geevarghese, a student in the School of Arts and Sciences at Tufts University. She participated in the Tufts Summer Scholars Program, funded through the Office of the Provost, which offers research apprenticeships to undergraduate students.

This work was supported by the National Eye Institute, part of the National Institutes of Health, and Healthpoint, Inc. A patent application related to the study has been filed by Tufts University.

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Sackler Researchers Probe Consequences of BPA Exposure

Thu, 02 Dec 2010 00:00:00 -0500

BOSTON (December 2, 2010)

Exposure to a ubiquitous environmental chemical during pregnancy may impair reproductive capacity of female offspring, according to a study published online in advance of print on December 2 in Environmental Health Perspectives. Fertility decreased over time in female mice that had been exposed during fetal and neonatal (perinatal) development to doses of bisphenol-A (BPA) that were lower than or equal to human environmental exposure levels.

“Mice exposed to BPA in the womb and during nursing subsequently had fewer successful pregnancies and delivered fewer pups over the course of the study,” reported one of the study’s co-senior authors, Ana M. Soto, MD, professor of anatomy and cellular biology at Tufts University School of Medicine (TUSM) and member of the cell, molecular and developmental biology program faculty at the Sackler School of Graduate Biomedical Sciences.

At the highest of three doses tested, only 60% of the BPA-exposed mice had four or more deliveries over a 32-week period, compared with 95% in the unexposed control group. Decline of the reproductive capacity of the female mice in this study was not obvious at first pregnancy, when the animals were very young, but manifested later in life with a decline in number of pups born per delivery.

“This finding is important because standard tests of reproductive toxicology currently consist of assessing the success of a first pregnancy in young animals. If subsequent pregnancies are not examined, relevant effects may be missed,” said co-senior author Beverly S. Rubin, PhD, associate professor of anatomy and cellular biology at TUSM and member of the cell, molecular and developmental biology and neuroscience program faculties at the Sackler School.

“In addition, the infertility effect of BPA was dose-specific in our study. The lowest and highest doses we tested both impaired fertility, while the intermediate dose did not. This phenomenon, called non-monotonicity, is a common characteristic of hormone action. In other words, chemicals have to be tested at a variety of doses in order to avoid false “no effect” results,” added co-senior author Carlos Sonnenschein, MD, professor of anatomy and cellular biology at TUSM and member of the cell, molecular and developmental biology program faculty at the Sackler School.

“BPA has effects that mimic those of estrogen, a natural hormone. Fetal and neonatal exposure to BPA has been shown to have other hormone-related effects in rodents, including increased risk of mammary and prostate cancers, altered behavior, and obesity. BPA has been found in the urine of over 92% of Americans tested, with higher levels in children and adolescents relative to adults. It has also been detected in human maternal and fetal plasma,” said co-first author Perinaaz R. Wadia, PhD, a research associate in the Soto/Sonnenschein laboratory at TUSM.

“Our findings are potentially of great relevance to humans because BPA is used in the production of materials people are exposed to every day, such as polycarbonate plastics and the resins used to coat the inside of food and beverage cans,” said co-first author Nicolas J. Cabaton, PhD, formerly a post-doctoral fellow in the Soto/Sonnenschein laboratory at TUSM and now at the French National Institute for Agricultural Research (INRA).

The authors compared the effects of BPA to those of diethylstilbestrol (DES), a hormonally active chemical that is known to have caused reproductive impairment in women exposed during fetal life, and concluded that the effects of these two chemicals on fertility were comparable. Similar to BPA, low doses of DES had failed to cause obvious reproductive problems when evaluated only at first pregnancy as in the standard tests used by regulatory agencies to determine toxicity.

The three doses of BPA tested are within the range of human exposure and below the Environmental Protection Agency (EPA) reference dose (i.e., the maximal acceptable daily dose). “Our results suggest that a more sensitive test, like the one used in this report should be adopted by regulatory agencies in order to uncover the true risk and possible epigenetic effects of suspected endocrine disruptors,” said Soto.

Additional authors include Daniel Zalko, DVM, PhD, French National Institute for Agricultural Research (INRA), Cheryl M. Schaeberle, BS, laboratory coordinator in the Soto/Sonnenschein lab; Michael H. Askenase, BS, formerly a research technician in the Soto/Sonnenschein lab; Jennifer L. Gadbois, RN, Andrew P. Tharp, BS, and Gregory S. Whitt, BS, all research technicians in the Soto/Sonnenschein lab in the department of anatomy and cellular biology at TUSM.

This study was supported by the National Institute of Environmental Health Sciences, part of the National Institutes of Health.

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Anthony P Monaco, MD, PhD Selected as Tufts' President

Tue, 30 Nov 2010 06:47:00 -0500

Sackler Faculty Member and Trainees Uncover New Insights in Breast Cancer

Tue, 23 Nov 2010 18:17:00 -0500

BOSTON (November 23, 2010)

Breast cancer stem cells (CSCs), the aggressive cells thought to be resistant to current anti-cancer therapies and which promote metastasis, are stimulated by estrogen via a pathway that mirrors normal stem cell development. Disrupting the pathway, researchers were able to halt the expansion of breast CSCs, a finding that suggests a new drug therapy target. The study, done in mice, is published in the Proceedings of the National Academy of Sciences (PNAS) Early Edition this week.

“A critical aspect of our work was to discover that estrogen could promote breast cancer growth by modulating the proportion of breast CSCs. Since CSCs were not directly sensitive to estrogen, it wasn’t clear how estrogen could affect their numbers. However, we found that hormone-sensitive cancer cells can communicate with CSCs to regulate their numbers. By disrupting the interaction between cancer cell populations we were able to prevent tumor growth,” said Charlotte Kuperwasser, PhD, associate professor in the anatomy and cellular biology and radiation oncology departments at Tufts University School of Medicine, and member of the genetics and cell, molecular & developmental biology program faculties at the Sackler School of Graduate Biomedical Sciences at Tufts.

“Interestingly, this signaling pathway involves many of the same players that control normal stem cell biology, raising a more general possibility that CSCs in other tumors might be regulated by the mechanisms guiding normal development,” said Kuperwasser.

Kuperwasser and colleagues from MIT and Harvard used a mouse model to examine the behavior of cancerous human breast tissue with a method that mimics the human body more closely than standard mouse models. The researchers first examined estrogen’s effect on breast CSC growth, finding that estrogen caused breast CSC numbers to increase by nearly 800 percent. Since few breast CSCs contain estrogen receptors, the researchers suspected that estrogen’s actions were through a signaling mechanism from nearby cells that express the receptors.

“When nearby cells were exposed to estrogen, they secreted 14 times more FGF9, a signaling protein that drives CSC proliferation. When we blocked the FGF pathway with a small molecule inhibitor, we saw loss of CSC growth, tumorspheres generation, and even tumor formation. We then linked FGF signaling to the Tbx3 signaling axis, which is also important for embryonic mammary gland development,” said first author Christine Fillmore, PhD, a 2009 graduate of the genetics program at the Sackler School and currently a research fellow in genetics at Children’s Hospital Boston.

“These results show that interfering with this signaling pathway is a promising strategy for targeting breast CSCs. We are hopeful that the improved understanding of the mechanisms that promote breast CSCs will lead to the development of drugs that can be used to halt CSC proliferation,” said Kuperwasser.

Kuperwasser also leads a laboratory at the Molecular Oncology Research Institute (MORI) at Tufts Medical Center, which is dedicated to the exploration of the molecular mechanisms of cancer and the translation of findings into the clinic.

Additional authors on the study include Piyush Gupta, PhD, formerly of the Broad Institute, and now a member of the Whitehead Institute for Biomedical Research as well as an assistant professor of biology at MIT; Jenny Rudnick, a graduate student in the cell, molecular & developmental biology program at the Sackler School and member of the Kuperwasser lab at MORI; Silvia Caballero, formerly a participant in the Post-baccalaureate Research Education Program at the Sackler School, and now at Cornell University; Patricia Keller, PhD, a postdoctoral fellow in the department of anatomy and cellular biology at TUSM and member of Kuperwasser’s lab at MORI; and Eric Lander, PhD, founding director of the Broad Institute, professor of biology at MIT, and professor of systems biology at Harvard Medical School.

This study was supported by the Breast Cancer Research Foundation, the Raymond and Beverly Sackler Foundation, and by the National Cancer Institute, part of the National Institutes of Health; and by a Broadway on Beachside Postdoctoral Fellowship from the New England Division of the American Cancer Society to Patricia Keller. The Post-baccalaureate Research Education Program at the Sackler School is funded through the Division of Minority Opportunities in Research program of the National Institute of General Medical Sciences, an institute of the National Institutes of Health, and by the Sackler School.

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New Lost Cost Method of Vaccine Delivery Shows Promise

Tue, 16 Nov 2010 00:00:00 -0500

BOSTON and GRAFTON, MA (November 16, 2010)

Researchers have developed a promising new approach to vaccination for rotavirus, a common cause of severe diarrheal disease that is responsible for approximately 500,000 deaths among children in the developing world every year. In a study published in the November issue of Clinical and Vaccine Immunology, a vaccine delivered as nasal drops effectively induced an immune response in mice and protected them from rotavirus infection. The new vaccine delivery system has also been tested successfully and found to be heat stable with tetanus and is currently being tested with diphtheria and pertussis.

The team from the Cummings School of Veterinary Medicine at Tufts University and Tufts University School of Medicine collaborated with researchers from Boston and Tulane Universities to test the effectiveness of immunization with harmless bacteria that were engineered to display rotavirus protein.

“The new vaccine, in conjunction with an agent that enhances immunity, induced sufficient antibody formation against rotavirus to protect mice against infection when the mice were exposed to rotavirus three weeks after their third immunization,” explained John E. Herrmann, PhD, research professor in the infectious diseases division of the department of biomedical sciences at the Cummings School of Veterinary Medicine at Tufts University and the senior author of the published study.

“We created the rotavirus vaccine using a harmless bacterium called Bacillus subtilis (B. subtilis), which we can modify to display on its surface or in its cytoplasm proteins from infectious bacteria and viruses. When people are exposed to these proteins, they develop antibodies against them and therefore become immune to the bacteria and viruses,” said the study’s first author Sangun Lee, PhD, DVM, research associate at the Cummings School. “The B. subtilis bacteria are so harmless that they are part of the normal diet in several Asian countries.”

“The vaccine with the Bacillus bacteria is very inexpensive to produce in large quantities and, unlike most traditional vaccines, requires no special purification steps before use. As a result, the cost of vaccine production is unusually low,” explained Saul Tzipori, BVSc (DVM), DSc, PhD, Agnes Varis University Chair in Science and Society, distinguished professor of microbiology and infectious diseases, director of the infectious diseases division of the department of biomedical sciences at the Cummings School and member of the cellular & molecular physiology program at the Sackler School of Graduate Biomedical Sciences at Tufts. These findings are consistent with the team’s previous studies in which they demonstrated that B. subtilis bacteria displaying a fragment of tetanus toxin protein completely protect mice from tetanus. Tetanus vaccines have been stored for more than a year at 113ºF without any loss of potency, a property that may be common to all B. subtilis vaccines.

Vaccines currently available have to be stored in refrigerators or freezers until the moment they are administered. This cold chain is difficult and costly to maintain. In many parts of the world, there is insufficient refrigeration or electricity to keep vaccines cold. The lack of refrigeration combined with the lack of trained personnel, especially in rural areas in developing countries, make it impossible for many children and adults to be vaccinated against standard infections, such as tetanus, rotavirus, diphtheria, pertussis (whooping cough) and other diseases.

“In addition to being heat-stable and low-cost, the B. subtilis vaccines are given in the form of nasal drops or spray. A needle-free approach to vaccination is particularly advantageous in developing countries where clean needles and syringes and trained personnel are not always available,” said team leader Abraham L. (Linc) Sonenshein, PhD, professor and acting chair of molecular biology and microbiology at TUSM and member of the genetics and microbiology program faculties at the Sackler School of Graduate Biomedical Sciences at Tufts.

“This vaccine project is still in the developmental stage,” he continued. “The next major step for these vaccines is to show that they are safe and work well in humans, and then to extend the rotavirus and tetanus vaccine technology to include diphtheria, pertussis and other infectious diseases. Those diseases cause tens of thousands of deaths, particularly in newborns and in South-East Asia. We are actively looking for partners in the US and around the world to help us pursue our goal of reaching the point where many childhood and adult vaccines can be manufactured in a way that avoids the need for injection or refrigeration. Jerry Keusch of Boston University School of Public Health and I started this project 15 years ago and it has taken a long time to reach the stage where we now have effective needle-free vaccines. The technology has now advanced enough that we can expect to be successful with many other vaccines in a short time frame.”

Additional authors include Boris R. Belitsky, PhD, assistant research professor in the department of molecular biology and microbiology at TUSM; James P. Brinker, M.P.H, in the department of biomedical sciences at the Cummings School; Kathryn O. Kerstein, MS, senior research associate in the department of molecular biology and microbiology at TUSM; David W. Brown, PhD, DVM, clinical assistant professor in the infectious diseases division of the department of biomedical sciences at the Cummings School; Gerald T. Keusch, MD, professor in the department of international health at Boston University School of Public Health, professor of medicine at Boston University School of Medicine and U.S. chairman of the Indo-U.S. Vaccine Action Program at the National Institutes of Health; and John D. Clements, PhD, professor and chair of the department of microbiology and immunology at Tulane University Health Sciences Center.

This study was supported by a grant from the Grand Challenges in Global Health program of the Bill and Melinda Gates Foundation, and this grant was administered by the Foundation for the National Institutes of Health. Patent applications related to the discoveries reported in these studies have been filed by Tufts University.

Lee S, Belitsky BR, Brinker JP, Kerstein KO, Brown DW, Clements JD, Keusch GT, Tzipori S, Sonenshein AL, Herrmann JE. Clinical and Vaccine Immunology.. 2010 (November); 17 (11): 1647-1655. “Development of a Bacillus subtilis-based rotavirus vaccine.” DOI: 10.1128/CVI/00135-10.

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Novel Small Molecules Identified as Possible Anti-cancer Agents

Wed, 03 Nov 2010 07:28:00 -0400

BOSTON (3:00 p.m. ET, November 1, 2010) — A class of compounds that interferes with cell signaling pathways may provide a new approach to cancer treatment, according to a study published online this week in the Proceedings of the National Academy of Sciences (PNAS) Early Edition. The compounds, called PITs (non-phosphoinositide PIP3 inhibitors), limited tumor growth in mice by inducing cell death.

“PITs cause cells to self-destruct by interfering with the signaling pathways that regulate cell survival. As compounds that promote cell death, PITs show promise in halting the harmful, unwanted growth characteristic of cancer,” said senior author Alexei Degterev, PhD, assistant professor in the biochemistry department at Tufts University School of Medicine (TUSM) and member of the biochemistry program faculty at the Sackler School of Graduate Biomedical Sciences at Tufts.

Degterev teamed up with colleagues at TUSM, Northeastern University, Massachusetts General Hospital, Harvard Medical School, and the National Chemical Laboratory in Pune, India, to identify compounds that could disrupt a cell signaling molecule called PIP3. Out of 50,000 small molecules screened, the team identified two that inhibited PIP3.

“We tested the more stable of these two molecules in mice and found that it inhibited tumor growth and induced cancer cell death,” said co-first author Benchun Miao, PhD, formerly a postdoctoral associate in the biochemistry department at TUSM and fellow in Degterev’s lab and now a postdoctoral associate in the Nutrition and Cancer Laboratory at the Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University.

“We also found that PITs showed an even stronger anti-tumor effect in cells with high PIP3 levels. In humans, these high-PIP3 cells are responsible for aggressive forms of cancer such as glioblastoma,” said co-first author Igor Skidan, PhD, formerly a postdoctoral fellow in the department of pharmaceutical sciences at Northeastern University and now a senior scientist at Morphotek, Inc.

According to Degterev, PITs are a promising and relatively unexplored approach to cancer treatment. He says that PITs are a new class of compounds that inhibit PIP3, positioned at an early point in a cell signaling pathway over-activated in many human tumors. The study also presents a methodology for identifying other molecules similar to PITs. Degterev hopes that this approach will help researchers isolate other new compounds that halt cancer growth.

“We are not yet at the stage of considering PITS as leads for therapeutics. Our next focus, with our collaborators at National Chemical Laboratory, will be to develop PITS to be more effective,” says Degterev.

This study was supported by the Smith Family Awards for Excellence in Biomedical Research, a National Institute on Aging Mentored Research Scientist Career Development Award, a US Army Innovator Award; as well as the National Cancer Institute and the National Institute on Aging, both parts of the National Institutes of Health. Patent applications related to the discoveries described in this paper have been filed by Tufts University, Harvard University, and the National Chemical Laboratory, India.

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APC Linked to Autism and Mental Retardation

Mon, 23 Aug 2010 00:00:00 -0400

BOSTON (August 23, 2010) — A clue to the causes of autism and mental retardation lies in the synapse, the tiny intercellular junction that rapidly transfers information from one neuron to the next. According to neuroscientists at Tufts University School of Medicine, with students from the Sackler School of Graduate Biomedical Sciences at Tufts, a protein called APC (adenomatous polyposis coli) plays a key role in synapse maturation, and APC dysfunction prevents the synapse function required for typical learning and memory. The findings are published in the August 18 issue of The Journal of Neuroscience.

“Both sides of the synapse are finely tuned for efficient transmission; an imbalance on either side can negatively impact function, resulting in cognitive deficits. Our study reveals that APC forms a key protein complex in the postsynaptic neuron that also provides signals to direct synapse maturation in the presynaptic neuron, ensuring that the two sides of the synapse mature in concert to provide optimal function,” said senior author Michele H. Jacob, PhD, professor in the department of neuroscience at Tufts University School of Medicine. Jacob is also a member of the cell, molecular and developmental biology; cellular and molecular physiology; and neuroscience program faculties at the Sackler School of Graduate Biomedical Sciences at Tufts.

In the in vivo study, the team blocked APC function and found that synaptic levels of the cell adhesion proteins neuroligin and neurexin dropped considerably. Without normal levels of these proteins, synapses were less mature both structurally and functionally. Mutations in the genes for neuroligin and neurexin are associated with autism in humans, but until now, little was known about the mechanisms responsible for localizing these proteins at the synapse.

“Our laboratory study is the first to show that APC is needed to recruit neuroligin and neurexin to the synapse. This finding provides new insights into the mechanisms required for proper synapse function as well as molecular changes at the synapse that likely contribute to autistic behaviors and learning deficits in people with APC loss of function gene mutations,” said Jacob.

“Our study also sheds light on a poorly-understood but essential process, the cross-talk that occurs between presynaptic and postsynaptic neurons. When we perturbed APC function on the postsynaptic side, we saw changes on both sides of the synapse, indicating that APC organizes a protein complex that communicates against the normal flow of traffic,” said first author Madelaine Rosenberg, PhD, an affiliate of the department of neuroscience at TUSM.

The research team’s next step is to examine the behavioral and cognitive changes that occur when APC is deleted in neurons of the mammalian brain. They have developed a new mouse model that will allow them to investigate how the loss of APC function leads to synaptic changes and impaired learning and memory.

Additional authors are Fang Yang, PhD, a research associate in the department of medicine at TUSM; Jesse Mohn, a PhD candidate in the cell, molecular, and developmental biology program at Sackler and member of Jacob’s lab; and Elizabeth Storer, a PhD candidate in the neuroscience program at Sackler and member of Jacob’s lab.

This study was funded by the National Institute of Neurological Disorders and Stroke (NINDS), part of the National Institutes of Health, and the Tufts Center for Neuroscience Research. The Tufts Center for Neuroscience Research, itself, is supported by NINDS and by Tufts University School of Medicine and Tufts Medical Center.

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Keys to miRNA Processing Revealed

Mon, 16 Aug 2010 00:00:00 -0400

BOSTON (August 16, 2010) — Researchers at Tufts University School of Medicine and Tufts Medical Center have identified an RNA sequence that promotes increased numbers of specific microRNAs (miRNAs), molecules that regulate cell growth, development, and stress response. The discovery helps researchers understand the links between miRNA expression and disease, including heart disease and cancer. The findings are published in the August 13 issue of Molecular Cell.

“A growing body of evidence shows that abnormal expression of miRNAs can contribute to human diseases such as heart disease and cancer. A better understanding of how miRNAs are generated and how they regulate genes may provide important insights into the mechanisms of physiological disorders such as heart disease and cancer,” said senior author Akiko Hata, PhD, associate professor in the department of biochemistry at Tufts University School of Medicine (TUSM) and a member of the biochemistry and cell, molecular and developmental biology program faculties at the Sackler School of Graduate Biomedical Sciences at Tufts.

miRNAs are initially formed as a long sequence of RNA called the primary miRNA. This molecule undergoes several steps to transform it into mature miRNA. Once formed, the mature miRNAs regulate gene expression by silencing or activating target genes. More than 700 human miRNAs with various functions are currently known.

Hata and colleagues previously found that the processing of some miRNAs could be regulated in response to cellular signals from a specific signaling pathway. In the current study, Hata and colleagues found that most of the miRNAs regulated by this signaling pathway share a common RNA sequence. When this RNA sequence was mutated, the signaling pathway no longer regulated miRNA processing. Conversely, when the RNA sequence was introduced into a new miRNA, the miRNA became responsive to the signaling pathway.

“An enzyme called Drosha is needed for miRNA processing. Our previous studies determined that proteins called Smads are also required for the processing of some miRNAs in response to cellular signals. Now, we have identified the RNA sequence that recruits Drosha and Smads for miRNA processing in response to the signaling pathway,” said first author Brandi Davis, PhD, a 2010 graduate of the biochemistry program at the Sackler School and a postdoctoral fellow in Hata’s lab. “We knew that Smad proteins regulate gene expression by binding to DNA. Our current study is exciting because it shows that Smads play an additional role, controlling miRNA expression by binding to the structurally different RNA.”

While miRNAs were first discovered in 1993, scientists did not link them to gene regulation until nearly ten years later. Now, scientists are working to understand how miRNA expression is controlled, what genes miRNAs target, and how varying levels of miRNAs are related to human disease, particularly heart disease and cancer.

“Scientists are just beginning to understand the roles of miRNA in the body, and this study adds another piece to the puzzle. By investigating the mechanisms that govern which genes are translated and which genes are silenced, we can begin to understand how miRNAs impact the progression of cardiovascular diseases and cancer,” said Hata.

Hata is also the director of the Molecular Signaling Laboratory in the Molecular Cardiology Research Institute (MCRI) at Tufts Medical Center. The MCRI, with investigators and physician-scientists from Tufts University School of Medicine and Tufts Medical Center, is dedicated to the study of the molecular mechanisms of human cardiovascular disease, the translation of bench findings to new bedside strategies for diagnosis and therapy, and the mentoring of MD and PhD trainees committed to a career in academic cardiovascular research.

Additional authors on the study are Aaron Hilyard, BS, and Peter Nguyen, MBS, both research associates in the Molecular Signaling Laboratory in the MCRI; and Giorgio Lagna, PhD, an investigator in the MCRI at Tufts Medical Center and an assistant professor in the department of medicine at TUSM.

This study was supported by the National Heart, Lung, and Blood Institute, part of the National Institutes of Health, and the American Heart Association.

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Nanoparticles to Combat Degenerative Eye Disease

Mon, 16 Aug 2010 00:00:00 -0400

BOSTON (August 16, 2010) — In one of only two studies of its kind, a study from researchers at Tufts University School of Medicine and the Sackler School of Graduate Biomedical Sciences at Tufts demonstrates that non-viral gene therapy can delay the onset of some forms of eye disease and preserve vision. The team developed nanoparticles to deliver therapeutic genes to the retina and found that treated mice temporarily retained more eyesight than controls. The study, published online in advance of print in Molecular Therapy, brings researchers closer to a non-viral gene therapy treatment for degenerative eye disorders.

“Our work shows that it is possible to attain therapeutic results using non-viral gene delivery methods, specifically, nanoparticles. Nanoparticles, which are small enough to penetrate cells and stable enough to protect DNA, are capable of preventing retinal cell death and preserving vision,” said senior author Rajendra Kumar-Singh, PhD, associate professor of ophthalmology at Tufts University School of Medicine (TUSM) and member of the genetics; neuroscience; and cell, molecular, and developmental biology program faculties at the Sackler School of Graduate Biomedical Sciences at Tufts.

“The most common approach to gene therapy involves using a virus to deliver DNA to cells. While viruses are very efficient carriers, they can prompt immune responses that may lead to inflammation, cancer, or even death. Non-viral methods offer a safer alternative, but until now, efficiency has been a significant barrier,” said Kumar-Singh.

In a model simulating the progression of human retinal degeneration, the researchers treated mice with nanoparticles carrying a gene for GDNF (Glial Cell Line-Derived Neurotrophic Factor), a protein known to protect the photoreceptor cells in the eye. Retinas treated with the GDNF-carrying nanoparticles showed significantly less photoreceptor cell death than controls. Preservation of these cells resulted in significantly better eyesight in the treatment group seven days after treatment, compared to controls.

The protection conferred by the GDNF-carrying nanoparticles was temporary, as tests fourteen days after treatment showed no difference in eyesight between treated mice and controls.

“The next step in this research is to prolong this protection by adding elements to the DNA that permit its retention in the cell. Bringing forth a more potent and enduring result will move us closer to clinical application of non-viral gene therapy,” said Kumar-Singh.

AMD, which results in a loss of sharp, central vision, is the number one cause of visual impairment among Americans age 60 and older. Retinitis pigmentosa, an inherited condition characterized by night blindness and loss of peripheral vision, affects approximately 1 in 4,000 individuals in the United States.

Additional authors on the study are first author Sarah Parker Read, an MD/PhD candidate at TUSM and Sackler and member of Kumar-Singh’s lab, and Siobhan Cashman, PhD, research assistant professor in the department of ophthalmology at TUSM and member of Kumar-Singh’s lab.

In a previous study, this same team of researchers developed the gene delivery method used in this research. The researchers showed that a peptide called PEG-POD, which compacts DNA into nanoparticles, delivers genes to the retina more efficiently than other non-viral carriers.

This study was supported by grants from The Ellison Foundation; the National Eye Institute, part of the National Institutes of Health; the Virginia B. Smith Trust; and grants to the Department of Ophthalmology at Tufts University from the Lions Eye Foundation and Research to Prevent Blindness. Sarah Parker Read is part of the Sackler/TUSM Medical Scientist Training Program, which is funded by the National Institute of General Medical Sciences, part of the National Institutes of Health.

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New Targets for Anti-Angiogenesis Drugs

Mon, 16 Aug 2010 00:00:00 -0400

BOSTON (August 16, 2010, 9:00 a.m. EDT) — A new study describes how a carbohydrate-binding protein, galectin-3, promotes angiogenesis, the growth of new blood vessels. Targeting the protein, scientists identified two approaches that significantly reduced angiogenesis in mice. These discoveries, published online August 16 in The Journal of Experimental Medicine, may lead to novel treatments for diseases caused by excessive angiogenesis, including age-related macular degeneration, cancer, and diabetes.

When the body needs to expand its network of blood vessels, cells release molecular signals called growth factors that prompt angiogenesis. While this process is key for normal growth, development, and wound healing, it can be harmful when blood vessels supply tumors or other diseased tissue, or when excessive blood vessel growth encroaches on surrounding tissues.

A growing body of research indicates that a protein called galectin-3 promotes angiogenesis, indicating that it may be a valuable target for drugs that halt harmful blood vessel growth. Until now, though, scientists did not understand how galectin-3 promotes angiogenesis.

Led by Noorjahan Panjwani, PhD, researchers propose a mechanism that explains how galectin-3 brings about angiogenesis. Panjwani is a professor in the department of ophthalmology at Tufts University School of Medicine and a member of the biochemistry and cell, molecular and developmental biology program faculties at the Sackler School of Graduate Biomedical Sciences.

“Our study shows that galectin-3 protein binds to glycans (carbohydrate portions) of specific cell-adhesion proteins, the integrins, to activate the signaling pathways that bring about angiogenesis. This improved understanding may provide a more targeted approach to preventing harmful angiogenesis,” said Panjwani.

“We found that application of a galectin-3 inhibitor significantly reduced angiogenesis in mice. We also found that preventing galectin-3 from binding with the integrins reduced angiogenesis,” said first author Anna Markowska, a PhD student in the biochemistry program at the Sackler School of Graduate Biomedical Sciences at Tufts.

“By deciphering the mechanism of galectin-3 action, we were able to establish more than one therapeutic target. The more we know about how this pathway works, the more options we have for potential treatments,” said Panjwani.

Panjwani’s lab is dedicated to understanding the cell biological and biochemical mechanisms of wound healing and angiogenesis, specifically for the purpose of developing improved treatments for blinding eye diseases. Panjwani’s research is also focused on Acanthamoeba keratitis, a rare and painful parasitic infection of the cornea that can affect contact lens wearers. She is currently working on strategies to protect against the infection and is developing a test that identifies at-risk individuals by sampling their tears.

Fu-Tong Liu, MD, PhD, professor and chair of the department of dermatology at University of California Davis School of Medicine, is also an author of the study.

This work was funded by the National Eye Institute, part of the National Institutes of Health, the Massachusetts Lions Eye Research Fund, and Research to Prevent Blindness.

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Behind the Secrets of Silk

Sat, 31 Jul 2010 00:00:00 -0400

New Research Highlights the Potential of Silk

Tougher than a bullet-proof vest yet synonymous with beauty and luxury, silk fibers are a masterpiece of nature whose remarkable properties have yet to be fully replicated in the laboratory. Thanks to their amazing mechanical properties as well as their looks, silk fibers have been important materials in textiles, medical sutures, and even armor for 5,000 years. Silk spun by spiders and silk worms combines high strength and extensibility. This one-two punch is unmatched by synthetics, even though silk is made from a relatively simple protein processed from water.

In recent years scientists have begun to unravel the secrets of silk. In the July 30, 2010, issue of the journal Science, Tufts biomedical engineering researchers Fiorenzo Omenetto, PhD, and David Kaplan, PhD, report that "Silk-based materials have been transformed in just the past decade from the commodity textile world to a growing web of applications in more high technology directions."

Fundamental discoveries into how silk fibers are made have shown that chemistry, molecular biology and biophysics all play a role in the process. These discoveries have provided the basis for a new generation of applications for silk materials, from medical devices and drug delivery to electronics.

Edible Optics, Implantable Electronics

The Science paper notes that the development of silk hydrogels, films, fibers and sponges is making possible advances in photonics and optics, nanotechnology, electronics, adhesives and microfluidics, as well as engineering of bone and ligaments. Because silk fiber formation does not rely on complex or toxic chemistries, such materials are biologically and environmentally friendly, even able to integrate with living systems.

Down the silk road of the future, Kaplan and Omenetto believe applications could include degradable and flexible electronic displays for sensors that are biologically and environmentally compatible and implantable optical systems for diagnosis and treatment. Progress in "edible optics" and implantable electronics has already been demonstrated by Kaplan and Omenetto, John Rogers at the University of Illinois at Urbana-Champaign, and others.

Many challenges remain. Kaplan and Omenetto say that key questions include how to fully replicate native silk assembly in the lab, how best to mimic silk protein sequences via genetic engineering to scale-up materials production, and how to use silk as a model polymer to spur new synthetic polymer designs that mimic natural silk's green chemistry.

Techniques for reprocessing natural silk protein in the lab continue to advance. Silks are also being cloned and expressed in a variety of hosts, including E. coli bacteria, fungi, plants and mammals, and through transgenic silkworms.

One day, efficient transgenic plants could be used to crop silk in much the same way that cotton is harvested today, the Tufts researchers note in their paper. In some regions, silk production might create a new microeconomy, as demand grows and production techniques improve.

"Based on the recent and rapid progression of silk materials from the ancient textile use into a host of new high-technology applications, we anticipate growth in the use of silks in a wide platform of applications will continue as answers to these remaining questions are obtained," say Omenetto and Kaplan.

Kaplan is chair of the Biomedical Engineering Department at Tufts School of Engineering and the Stern Family Professor in Engineering. He also directs the NIH Tissue Engineering Resource Center that involves Tufts and Columbia University and is a member of the Cell, Molecular & Developmental Biology Program at the Sackler School. His work lies at the interface between biology and materials science and engineering, and he has been studying novel biomaterials, many of them silk-based, for 30 years. Professor of Biomedical Engineering Fiorenzo Omenetto is a frequent collaborator with Kaplan who has pioneered silk optics and use of silk as a green material for photonics and other high tech applications.

Map of Herpes Virus Protein Suggests New Drug Therapy

Tue, 06 Jul 2010 00:00:00 -0400

BOSTON (July 6, 2010) — The mechanism by which a herpes virus invades cells has remained a mystery to scientists seeking to thwart this family of viruses. New research funded by the National Institutes of Health and published online in advance of print in Nature Structural & Molecular Biology reveals the unusual structure of the protein complex that allows a herpes virus to invade cells. This detailed map of a key piece of the herpes virus “cell-entry machinery” gives scientists a new target for antiviral drugs.

“Most viruses need cell-entry proteins called fusogens in order to invade cells. We have known that the herpes virus fusogen does not act alone and that a complex of two other viral cell-entry proteins is always required. We expected that this complex was also a fusogen, but after determining the structure of this key protein complex, we found that it does not resemble other known fusogens,” said senior author Ekaterina Heldwein, PhD, assistant professor in the molecular biology and microbiology department at Tufts University School of Medicine. “This unexpected result leads us to believe that this protein complex is not a fusogen itself but that it regulates the fusogen. We also found that certain antibodies interfere with the ability of this protein complex to bind to the fusogen, evidence that antiviral drugs that target this interaction could prevent viral infection,” Heldwein continued. Heldwein is also a member of the biochemistry and molecular microbiology program faculties at the Sackler School of Graduate Biomedical Sciences at Tufts.

“Katya Heldwein’s work has resulted in a map of the protein complex needed to trigger herpes virus infection. The NIH Director's New Innovator Awards are designed to support such breakthroughs. This research not only adds to what we know about how herpes viruses infect mammalian cells, but also sets the stage for new therapeutics that restrict herpes virus’s access to the cell,” said Jeremy M. Berg, PhD, director of the National Institute of General Medical Sciences (NIGMS) at the National Institutes of Health.

“We hope that determining the structure of this essential piece of the herpes virus cell-entry machinery will help us answer some of the many questions about how herpes virus initiates infection. Knowing the structures of cell-entry proteins will help us find the best strategy for interfering with this pervasive family of viruses,” said first author Tirumala K. Chowdary, PhD, a postdoctoral associate in the department of molecular biology and microbiology at TUSM and member of Heldwein’s lab.

Currently, there is no cure for herpes viruses. Upon infection, the viruses remain in the body for life and can stay inactive for long periods of time. When active, however, different herpes viruses can cause cold sores, blindness, encephalitis, or cancers. More than half of Americans are infected with herpes simplex virus type 1 (HSV-1), which causes cold sores, by the time they reach their 20s. Currently, about one in six Americans is infected with herpes simplex virus type 2 (HSV-2), the virus responsible for genital herpes. Complications of HSV-2, a sexually-transmitted disease, include recurrent painful genital sores, psychological distress, and, if transmitted from mother to child, potentially fatal infections in newborn infants.

Heldwein teamed up with colleagues at University of Pennsylvania and used x-ray crystallography along with cell microscopy techniques to study the structure and function of this cell-entry protein complex in HSV-2. Heldwein is currently developing a molecular movie that illustrates how herpes virus enters the cell.

Additional authors are Tina Cairns, PhD, a research specialist; Doina Atanasiu, a research associate; and Gary Cohen, PhD, professor and chair, all in the department of microbiology at the University of Pennsylvania School of Dental Medicine; and Roselyn Eisenberg, PhD, professor in the department of microbiology at the University of Pennsylvania School of Veterinary Medicine.

This work was funded by the Office of the Director of the National Institutes of Health, through a New Innovator Award in 2007 to Ekaterina Heldwein. The New Innovator Awards, part of the NIH Roadmap for Medical Research initiative, are awarded to support early-career scientists who take innovative – and potentially transformative – approaches to major challenges in biomedical research. The work was also funded by the National Institute of Allergy and Infectious Diseases, part of the National Institutes of Health, and the Pew Scholar Program in Biomedical Sciences.

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Endocrine-Disrupting Chemicals Pose Cancer Risk

Tue, 25 May 2010 00:00:00 -0400

BOSTON (May 25, 2010) — Longtime environmental health researchers at Tufts University School of Medicine describe the carcinogenic effects of endocrine-disrupting chemicals (EDCs), ubiquitous chemicals that have hormone-like effects in the body. In a review article published online May 25 in Nature Reviews Endocrinology, the researchers express the need for more complex strategies for studying how these chemicals affect health but report that ample evidence already supports changing public health and environmental policies to protect the public from exposure to EDCs.

“The strength and breadth of existing research on the negative effects of EDCs, including bisphenol A, warrants immediate action to reduce EDC exposure, particularly among the developing fetus and women of reproductive age,” said author Carlos Sonnenschein, MD, professor in the department of anatomy and cellular biology at Tufts University School of Medicine (TUSM), and faculty member in the Cell, Molecular & Developmental Biology Program at the Sackler School of Graduate Biomedical Sciences.

“Developing embryos ‘read’ environmental cues as a forecast of the outside world. These cues can affect the way certain genes are expressed and in this way alter the structure and function of organs. Studies in rodents show that EDCs can cause harm at much lower levels if exposure happens during organ formation as opposed to exposures during adulthood,” said author Ana Soto, MD, professor in the department of anatomy and cellular biology at TUSM, and also a member of the Cell, Molecular & Developmental Biology Program.

“The evidence indicates that exposure to BPA and other EDCs may contribute to diseases that manifest during adult life, such as increased cancer rates in the industrialized world. These chemicals have also been linked to obesity, altered behavior, and infertility,” continued Soto.

The researchers drew several key points from the body of observational, epidemiological, and animal research examining EDCs, emphasizing that embryos display an increased sensitivity to the chemicals. In particular, Soto and Sonnenschein focused on bisphenol A (BPA), a chemical they have spent 15 years investigating. BPA, which is found in plastic bottles, reusable food containers, and food cans, is ubiquitous in industrialized nations and is linked to cancer.

“EDCs act additively and their effects are dependent upon exposure and context, making them inherently complex to study. New mathematical modeling tools and computer simulations will provide a more precise understanding of how these chemicals interact with each other and within the body at different stages of life. That said, we already have ample evidence supporting policies that reduce exposure to EDCs, and we recommend rapid action to diminish these harmful environmental exposures,” said Sonnenschein.

In previous animal studies, Soto and Sonnenschein observed that exposure to even trace levels of BPA can increase cancer risk in adulthood. The pair also collaborated in proposing the tissue organization field theory of carcinogenesis and metastasis as an alternative to the currently-held somatic mutation theory, arguing that cancer is a tissue-based disease rather than a cell-based disease as proposed by the somatic mutation theory of carcinogenesis. Both authors are also members of the cell, molecular and developmental biology program faculty at the Sackler School of Graduate Biomedical Sciences at Tufts.

This work was supported by grants from The Parsemus Foundation and the National Institute of Environmental Health Sciences, part of the National Institutes of Health.

Soto AM, Sonnenschein C. Nature Reviews Endocrinology. 2010. “Environmental causes of cancer: endocrine disruptors as carcinogens.” Published online May 25, 2010, doi: 10.1038/nrendo.2010.87

About Tufts University School of Medicine and the Sackler School of Graduate Biomedical Sciences
Tufts University School of Medicine and the Sackler School of Graduate Biomedical Sciences at Tufts University are international leaders in innovative medical education and advanced research. The School of Medicine and the Sackler School are renowned for excellence in education in general medicine, biomedical sciences, special combined degree programs in business, health management, public health, bioengineering and international relations, as well as basic and clinical research at the cellular and molecular level. Ranked among the top in the nation, the School of Medicine is affiliated with six major teaching hospitals and more than 30 health care facilities. Tufts University School of Medicine and the Sackler School undertake research that is consistently rated among the highest in the nation for its impact on the advancement of medical science.

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Protein Regulates Enzyme Linked to Alzheimer's Disease

Fri, 21 May 2010 00:00:00 -0400

BOSTON (May 25, 2010) — Researchers at Tufts University School of Medicine have zeroed in on a protein that may play a role in the progression of Alzheimer’s disease. The team found that increasing levels of the protein (called GGA3) prevented the accumulation of an enzyme linked to Alzheimer’s. The strategy may lead to new treatments for the neurodegenerative disease. The findings were published online May 18 in The Journal of Biological Chemistry.

People with Alzheimer’s disease typically have higher levels of an enzyme called BACE1 in their brains. BACE1 produces a toxin that researchers have pinpointed as a cause of Alzheimer’s, and now, researchers have found a way to prevent BACE1 from accumulating in the brain.

“We have identified the protein that takes this enzyme to the cell’s garbage disposal for removal. Increasing levels of the protein allows more of the enzyme to be eliminated, possibly preventing the high levels seen in people with Alzheimer’s disease,” said senior author Giuseppina Tesco, MD, PhD, assistant professor in the department of neuroscience at Tufts University School of Medicine (TUSM), and member of the Neuroscience Program at the Sackler School of Graduate Biomedical Sciences.

Tesco and colleagues previously discovered that levels of the GGA3 protein were significantly lower in the brains of Alzheimer’s patients than those free of the disease. In the current in vitro study, the team also found, unexpectedly, that the GGA3 protein must bind with the regulatory protein ubiquitin in order to lower enzyme levels.

“This insight advances our understanding of the molecular mechanisms of Alzheimer’s disease. We hope that our approach will lead to new therapies that treat and prevent Alzheimer’s, which currently affects as many as 5.1 million Americans,” said Tesco. Tesco is also a member of the neuroscience program faculty at the Sackler School of Graduate Biomedical Sciences at Tufts, leading the Alzheimer’s disease research laboratory.

Alzheimer’s disease is a progressive neurodegenerative disorder that results in loss of memory and cognitive function. It is the most common cause of dementia in adults age 65 and over. Currently, prescription drugs are available that may slow the progression of the disease, but none of these medications are effective in stopping the progression of Alzheimer’s.

Co-first authors of the study are Eugene Kang, BA, MPH, a senior research technician in the department of neuroscience at TUSM and a member of Tesco’s lab; and Andrew Cameron, BA, a senior technician in the department of neuroscience at TUSM and a member of Tesco’s lab. Additional authors include Fabrizio Piazza, PhD, and Kendall Walker, PhD, both postdoctoral associates in the department of neuroscience at TUSM and members of Tesco’s lab.

This study was funded by the National Institute on Aging, part of the National Institutes of Health.

Kang EL, Cameron AN, Piazza F, Walker KR, Tesco G. The Journal of Biological Chemistry. 2010. “Ubiquitin Regulates GGA3-Mediated Degradation of BACE1.” Published online May 18, 2010, doi: 10.1074/jbc.M109.092742

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Cellular Mechanical Forces May Initiate Angiogenesis

Mon, 26 Apr 2010 00:00:00 -0400

BOSTON and CAMBRIDGE (April 26, 2010) — Pericytes, the contractile cells surrounding capillaries, may use mechanical forces to initiate angiogenesis, the “sprouting” of new blood vessels, according to researchers at Tufts University School of Medicine (TUSM) and the Massachusetts Institute of Technology (MIT). The study, published in Journal of Physics: Condensed Matter, is among the first to examine mechanical signaling by pericytes as a potential driver of angiogenesis, which is crucial in the progression of cancer, diabetic retinopathy, and age-related macular degeneration.

Previously, scientists have focused on the chemical signals that initiate angiogenesis and have developed drugs to alter these signals. Now, it appears that the mechanical signals from pericytes can also play a role in regulating the sprouting of new blood vessels.

“If we find that mechanical signaling, such as the force exerted by pericytes, initiates angiogenesis, we can explore ways of interfering with these signals. In this in vitro study, we found that pericytes generated contractions that physically altered the microvascular environment. In the body, such local contractions could serve as the initiating, mechanical signals that influence angiogenesis,” said co-senior author Ira Herman, PhD, professor of physiology at TUSM and member of the Cellular & Molecular Physiology and Cell, Molecular & Developmental Biology programs at the Sackler School of Graduate Biomedical Sciences.

“Depending on the circumstances, angiogenesis can either promote health or promote disease,” he continued. “Angiogenesis is required for early development and wound healing, but it can also feed cancerous tumors or cause vascular complications in the eye. Our goals are aimed at developing drugs that might enhance wound healing angiogenesis while preventing the harmful angiogenesis that leads to tumor growth or vision loss.”

Herman and team members at Tufts joined materials scientists and engineers at MIT in this interdisciplinary effort.

“This collaboration enabled us to quantify the role that mechanics plays in angiogenesis at the cellular level. We directly imaged and quantified the contraction these pericytes exerted to wrinkle the underlying membrane and examined how specific drugs amplified and mitigated this contractile force. These measurements allowed us to estimate how much pericytes contracted and stiffened the microvascular environment, sending mechanical signals to nearby cells,” said co-senior author Krystyn J. Van Vliet, PhD, associate professor of materials science and engineering at MIT.

The researchers isolated pericytes, using criteria Herman helped develop, and applied them to a silicone membrane. With an atomic force microscope, researchers at MIT measured the stiffness of the contracting pericytes and the consequent degree of wrinkling the pericytes caused in the membrane. Pericytes generated contractions that caused underlying membranes to shorten by an average of 38 percent.

The first authors of the study are Sunyoung Lee, PhD, and Adam Zeiger, a PhD candidate, both members of the laboratory for material chemomechanics in the department of materials science and engineering at MIT. Additional authors are John Maloney, a PhD candidate and member of Van Vliet’s laboratory for material chemomechanics in the department of materials science and engineering at MIT, and Maciej Kotecki, MD, PhD, a research associate in Herman’s laboratory in the department of physiology at TUSM.

Krystyn Van Vliet is also an associate professor in the department of biological engineering at MIT. Ira Herman is also a member of the faculty in cell, molecular and developmental biology and in the cell and molecular physiology program at the Sackler School of Graduate Biomedical Sciences at Tufts.

This study was partially funded by a National Science Foundation CAREER Award, the National Science Foundation (Van Vliet), and the National Eye Institute, part of the National Institutes of Health (Herman).

Lee S, Zeiger A, Maloney J, Kotecki M, Van Vliet KJ, Herman IM. Journal of Physics: Condensed Matter. 2010. 22 (194115). “Pericyte actomyosin-mediated contraction at the cell-material interface can modulate the microvascular niche.” Published online April 26, 2010, doi: 10.1088/0953-8984/22/19/194115

About the Massachusetts Institute of Technology
The Massachusetts Institute of Technology, a co-educational privately endowed research university, is dedicated to advancing knowledge and educating students in science, technology, and other areas of scholarship to serve the nation and world. The Institute has more than 900 faculty and 10,000 undergraduate and graduate students.

MIT’s commitment to innovation has led to a host of scientific breakthroughs and technological advances. Achievements include the first chemical synthesis of penicillin and vitamin A, the development of inertial guidance systems, modern technologies for artificial limbs, and the magnetic core memory that led to the development of digital computers. Sixty-three alumni, faculty, researchers and staff have won the Nobel Prizes.

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If you are a member of the media interested in learning more about this topic, obtaining a copy of the study, or speaking with Ira Herman, please contact Siobhan Gallagher at 617-636-6586 or siobhan.gallagher@tufts.edu. To speak with Krystyn Van Vliet, please contact Jen Hirsch at 617-253-1682 or jfhirsch@mit.edu.

Researchers Find New Pathway for Age-Related Macular Degeneration (Tufts Medical Center)

Mon, 12 Apr 2010 00:00:00 -0400

The original news release, issued by Tufts Medical Center, can be found here.

BOSTON (April 12, 2010) - Researchers at Tufts Medical Center and collaborators discovered a new biological pathway for advanced age-related macular degeneration (AMD) that implicates a role of the hepatic lipase gene, LIPC. This discovery will improve understanding of the disease by providing researchers another developmental pathway to explore for prevention and treatment. The paper, titled “Genome-Wide Association Study of Advanced Age-Related Macular Degeneration Identifies a Role of the Hepatic Lipase gene (LIPC)”, has been published in the Proceedings of the National Academy of Sciences, April 12, 2010.

In the multidisciplinary study led by Johanna M. Seddon, MD, ScM, Professor of Ophthalmology at Tufts University School of Medicine and Director of the Ophthalmic Epidemiology and Genetics Service at Tufts Medical Center, researchers genotyped samples from 979 advanced AMD cases and 1,709 controls using the Affymetrix 6.0 platform with replication in 5,789 cases and 4,234 controls in seven independent cohorts. The most significant gene association was a functional variant in the hepatic lipase (LIPC) gene.

Seddon and colleagues’ data showed that the LIPC gene variation decreased risk of AMD. This gene is involved in raising serum levels of high-density lipoprotein cholesterol (HDL). The association with LIPC and other new HDL genes implicated in their study may not be directly related to raising or lowering levels of HDL and other mechanisms could be involved. “Identifying disease pathways is an important step toward the goal of developing new therapies and preventing visual loss due to AMD,” said Dr. Seddon, a physician and macular degeneration specialist.

Coauthors were from collaborating institutions worldwide including Massachusetts General Hospital, Johns Hopkins University School of Medicine, University of Utah School of Medicine, Columbia University in New York, Washington University School of Medicine in St. Louis, MO, and University Paris in Creteil, France.

Advanced macular degeneration is the leading cause of blindness in the developed world among people over the age of 50. More than 15 million people in North America are currently affected by the disease.

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About Tufts Medical Center

Tufts Medical Center is an exceptional, not-for-profit, 451-bed academic medical center that is home to both a full-service hospital for adults and Floating Hospital for Children. Conveniently located in downtown Boston, the Medical Center is the principal teaching hospital for Tufts University School of Medicine. The New England Eye Center is the clinical department of ophthalmology for the Tufts Medical Center. The New England Eye Center has a national and international reputation for quality patient care, innovative research and teaching. The main office is within the Tufts Medical Center in downtown Boston but the Eye Center features community access via 7 satellite offices throughout Eastern Massachusetts. Floating Hospital for Children is the full-service children's hospital of Tufts Medical Center and the principal pediatric teaching hospital of Tufts University School of Medicine.

For more information, please visit www.tuftsmedicalcenter.org.

Nationally Recognized Evolutionary Biologist Named VP for Science Education (HHMI)

Wed, 07 Apr 2010 00:00:00 -0400

The original news release, issued by the Howard Hughes Medical Institute, can be viewed here .

Howard Hughes Medical Institute (April 7, 2010) - The Howard Hughes Medical Institute today announced that Sean Carroll, an award-winning scientist, author, and educator, will become the Institute’s vice president for science education.

Carroll will be responsible for directing HHMI’s portfolio of science education activities when he succeeds Peter J. Bruns in September. Bruns, a geneticist and former Cornell University faculty member, announced his retirement last year after nine years in the post.

“Sean is a gifted scientist who also displays an extraordinary talent for translating complicated scientific ideas in compelling, understandable ways to members of the public of all ages,” said Robert Tjian, HHMI president. “He is in a unique position to connect our scientific and educational programs.”

Carroll, an HHMI investigator since 1990 on the faculty of the University of Wisconsin-Madison, studies the development and evolution of animal form and is considered a leader in the field of evolutionary developmental biology, or evo-devo. By utilizing the tools of modern molecular biology and genetics, Carroll and his colleagues have revealed how changes in gene regulation during development shape the evolution of body parts and body patterns.

The 49-year-old Carroll is also widely known as a speaker and writer about scientific subjects for the general public. He is the author of six books, including Remarkable Creatures: Epic Adventures in the Origins of Species, a finalist for the 2009 National Book Award in non-fiction. He writes a monthly column (also called “Remarkable Creatures”) for the science section of The New York Times and has served as a consulting producer for the public television program NOVA distributed by WGBH in Boston. In March, Carroll received the 2010 Stephen Jay Gould Prize in recognition of his efforts to advance public understanding of evolutionary science.

“HHMI has had a big impact in shaping how science is taught, particularly at the undergraduate level. Colleges and universities are shaking up what they teach and HHMI has been a catalyst for that change. That’s a great legacy to join,” said Carroll.

HHMI is the nation's largest private supporter of science education. It has invested more than $1.6 billion to reinvigorate life science education at research universities, liberal arts colleges, and undergraduate-focused institutions, as well as to engage the nation's leading scientists in teaching through the HHMI professors program. Other notable initiatives include the Science Education Alliance, launched in 2007 as a national resource for the development and distribution of innovative science education materials and methods, and the Exceptional Research Opportunities Program (EXROP), which offers mentored research experiences to select undergraduates.

“I want to help other people have as much fun as I have,” said Carroll in describing his decision to take on the new role at HHMI. “That requires thinking about how to foster creativity and innovation on a larger scale. We all need inspiration, but how do we nourish curiosity and inspire an interest in science, particularly among young people? These are crucial challenges and I hope to promote the very positive role that science can play in our culture.”

Carroll traces his own fascination with science to a childhood interest in collecting snakes, noting in an interview with the journal Nature that they inspired both his first experiments (their choice of food) and sense of beauty (the patterns of their skin). Today, Carroll’s laboratory uses fruit flies—Drosophila melanogaster and its relatives—as models for understanding how new body patterns evolve over time.

In a series of studies published over the last several years, Carroll and his colleagues have traced the origin of new and complex body color patterns and pinpointed the mutations in gene regulatory elements responsible for changing when and where in the body genes are used. “We are now able to trace the genetic steps of evolution in unprecedented detail. What our work has revealed is that, in general, body parts and body patterns evolve through ‘teaching old genes new tricks,’ that is, using very old genes in new way,” he said.

Carroll is recognized as an exemplary teacher and last year received the Viktor Hamburger Outstanding Educator Prize from the Society for Developmental Biology. The prize, established in 2002 in honor of a major figure in embryology, honored Carroll’s contributions to the field but singled out his leadership as a mentor and educator. He is also a recipient of the Distinguished Service Award from the National Association of Biology Teachers. Along with David Kingsley, a fellow HHMI investigator, Carroll delivered the Institute’s 2005 Holiday Lectures on Science, “Evolution: Constant Change and Common Threads.”

A member of both the National Academy of Sciences and the American Academy of Arts and Sciences, Carroll graduated summa cum laude from the Washington University in St. Louis, Missouri, and received a Ph.D. in immunology from Tufts University, where he worked in David Stollar’s laboratory. Carroll did his postdoctoral research at the University of Colorado, Boulder, in the laboratory of Matt Scott (now an HHMI investigator at the Stanford University School of Medicine) where he began his explorations in embryology and the study of genes that control body organization in the developing fruit fly.

Carroll joined the faculty of the University of Wisconsin-Madison in 1987, and became a full professor in 1995. He is the Allan Wilson Professor of Molecular Biology, Genetics, and Medical Genetics. Carroll plans to maintain his laboratory at the University of Wisconsin-Madison.

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The Howard Hughes Medical Institute plays a powerful role in advancing scientific research and education in the United States. Its scientists, located across the country and around the world, have made important discoveries that advance both human health and our fundamental understanding of biology. The Institute also aims to transform science education into a creative, interdisciplinary endeavor that reflects the excitement of real research.

American Society for Microbiology Honors Ekaterina Heldwein (ASM)

Thu, 11 Mar 2010 00:00:00 -0500

The below news release is a copy; the original was issued by the American Society for Microbiology (ASM) and can be viewed here.

(March 11, 2010) - A 2010 American Society for Microbiology (ASM) Merck Irving S. Sigal Memorial Award is being presented to Ekaterina "Katya" Heldwein, PhD, Assistant Professor, Department of Molecular Biology and Microbiology, Tufts University, Boston, MA, for her research on herpesvirus entry mechanisms. Sponsored by Merck Research Laboratories, the Merck Irving S. Sigal Memorial Award is presented in memory of Irving S. Sigal, who was instrumental in the early discovery of therapies to treat HIV/AIDS, to recognize excellence in basic research in medical microbiology and infectious diseases.

Heldwein received her Ph.D. in biochemistry from the Oregon Health and Sciences University, Portland, where she stayed for a short postdoctoral fellowship. Her crystallographic studies on the bacterial protein BmrR revealed the first structure of any multidrug binding transcription regulator in the free state as well as bound to a drug and to DNA. This groundbreaking work was published in Cell and Nature and provided significant insight into the functions of BmrR.

Heldwein completed her second postdoctoral fellowship at Children's Hospital and Harvard Medical School, Boston, MA, where she studied viral pathogenesis. She focused specifically on herpesvirus entry mechanisms and her research showed the structure of HSV-1 gB. Her work provided unprecedented insight into the function of this critical fusion protein. Currently, she is working on the biochemical and biological structure of gB and other components of the viral entry apparatus.

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The Merck Irving S. Sigal Memorial Award will be presented during the 110th General Meeting of the ASM, May 23-27, 2010 in San Diego, CA. ASM is the world's oldest and largest life science organization and has more than 43,000 members worldwide. ASM's mission is to advance the microbiological sciences and promote the use of scientific knowledge for improved health and economic and environmental well-being.

Researchers Develop New Tool for Gene Delivery

Wed, 27 Jan 2010 00:00:00 -0500

BOSTON (January 27, 2010) — Researchers at Tufts University School of Medicine and the Sackler School of Graduate Biomedical Sciences at Tufts have developed a new tool for gene therapy that significantly increases gene delivery to cells in the retina compared to other carriers and DNA alone, according to a study published in the January issue of The Journal of Gene Medicine. The tool, a peptide called PEG-POD, provides a vehicle for therapeutic genes and may help researchers develop therapies for degenerative eye disorders such as retinitis pigmentosa and age-related macular degeneration.

“For the first time, we have demonstrated an efficient way to transfer DNA into cells without using a virus, currently the most common means of DNA delivery. Many non-viral vectors for gene therapy have been developed but few, if any, work in post-mitotic tissues such as the retina and brain. Identifying effective carriers like PEG-POD brings us closer to gene therapy to protect the retinal cells from degeneration,” said senior author Rajendra Kumar-Singh, PhD, associate professor of ophthalmology and adjunct associate professor of neuroscience at Tufts University School of Medicine (TUSM) and member of the genetics; neuroscience; and cell, molecular, and developmental biology program faculties at the Sackler School of Graduate Biomedical Sciences at Tufts.

Safe and effective delivery of therapeutic genes has been a major obstacle in gene therapy research. Deactivated viruses have frequently been used, but concerns about the safety of this method have left scientists seeking new ways to get therapeutic genes into cells.

“We think the level of gene expression seen with PEG-POD may be enough to protect the retina from degeneration, slowing the progression of eye disorders and we have preliminary evidence that this is indeed the case,” said co-author Siobhan Cashman, PhD, research assistant professor in the department of ophthalmology at TUSM and member of Kumar-Singh’s lab.

“What makes PEG-POD especially promising is that it will likely have applications beyond the retina. Because PEG-POD protects DNA from damage in the bloodstream, it may pave the way for gene therapy treatments that can be administered through an IV and directed to many other parts of the body,” said Kumar-Singh.

Kumar-Singh and colleagues used an in vivo model to compare the effectiveness of PEG-POD with two other carriers (PEG-TAT and PEG-CK30) and a control (injections of DNA alone).

“Gene expression in specimens injected with PEG-POD was 215 times greater than the control. While all three carriers delivered DNA to the retinal cells, PEG-POD was by far the most effective,” said first author Sarah Parker Read, an MD/PhD candidate at TUSM and Sackler and member of Kumar-Singh’s lab.

Age-related macular degeneration, which results in a loss of sharp, central vision, is the number one cause of vision loss in Americans age 60 and older. Retinitis pigmentosa, an inherited condition resulting in retinal damage, affects approximately 1 in 4,000 individuals in the United States.

This study was supported by grants from the National Eye Institute of the National Institutes of Health, the Foundation for Fighting Blindness, The Ellison Foundation, The Virginia B. Smith Trust, the Lions Eye Foundation, and Research to Prevent Blindness. Sarah Parker Read is part of the Sackler/TUSM Medical Scientist Training Program, which is funded by the National Institute of General Medical Sciences, part of the National Institutes of Health.

Read SP, Cashman SM, Kumar-Singh R. The Journal of Gene Medicine. 2010 (January). 12(1): 86-96. “A poly(ethylene) glycolylated peptide for ocular delivery compacts DNA into nanoparticles for gene delivery to post-mitotic tissues in vivo.” Doi: 10.1002/jgm.1415

About Tufts University School of Medicine and the Sackler School of Graduate Biomedical Sciences

Tufts University School of Medicine and the Sackler School of Graduate Biomedical Sciences at Tufts University are international leaders in innovative medical education and advanced research. The School of Medicine and the Sackler School are renowned for excellence in education in general medicine, biomedical sciences, special combined degree programs in business, health management, public health, bioengineering and international relations, as well as basic and clinical research at the cellular and molecular level. Ranked among the top in the nation, the School of Medicine is affiliated with six major teaching hospitals and more than 30 health care facilities. Tufts University School of Medicine and the Sackler School undertake research that is consistently rated among the highest in the nation for its impact on the advancement of medical science.

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Cell of Origin Identified for Common Type of Breast Cancer

Tue, 19 Jan 2010 00:00:00 -0500

BOSTON (January 19, 2010, 12:00 noon EST) — A study by researchers at Tufts University School of Medicine, the Sackler School of Graduate Biomedical Sciences at Tufts, and Tufts Medical Center improves our current understanding of the origins of breast cancer. The researchers propose a new model for breast cell differentiation that identifies two populations of progenitor cells, one of which appears to be the cell of origin for luminal-like breast cancer, the most common form of the disease. The study, published in the January 19 issue of Cancer Cell, identifies a possible target for breast cancer drugs.

Breast cancers are generally classified in one of two categories. Luminal-like cancers, which are sensitive to hormones, are the most common form of breast cancer and tend to grow more slowly. Basal-like cancers, which are not sensitive to hormones, are more aggressive and tend to have a poorer prognosis. While scientists have predicted that these cancers might arise from different types of progenitor cells, it has been difficult to identify these cells of origin.

A team of researchers led by Charlotte Kuperwasser and Philip Hinds identified different types of breast stem and progenitor cells using a novel mouse model. Previously, researchers had been unable to functionally distinguish between stem cells that make the entire mammary tissue and other progenitor cells due to the shared molecular features of these cell populations.

“It wasn’t clear that breast tissues did in fact contain functionally distinct progenitor cells. Our findings, however, show that luminal-like breast cancer originates from one type of progenitor cell, lobule progenitors, which are the self-renewing cells required to generate the milk-producing structures in breast tissue during pregnancy and lactation. Inhibiting a protein essential to these cells prevented the formation of breast tumors in mice,” said co-senior author Charlotte Kuperwasser, PhD, associate professor in the anatomy and cellular biology department at Tufts University School of Medicine (TUSM) and member of the cell, molecular, and developmental biology and genetics program faculties at Sackler.

The researchers discovered that this population of progenitor cells depends on the activity of a protein called cyclin D1 for self-renewal and differentiation. The team generated a mouse model with inactive cyclin D1 and the gene known to promote luminal-like breast cancer. Compared to controls, the mice lacking in cyclin D1 activity contained very few lobule progenitor cells and had an absence of luminal-like tumors.

“The effects of eliminating cyclin D1 activity were profound. Depriving the lobule progenitor cells of cyclin D1 prevented self-renewal, disrupted normal mammary differentiation, and blocked the formation of luminal-like tumors,” said co-senior author Philip Hinds, PhD, deputy director of the Tufts Medical Center Cancer Center. He is also a professor in the radiation oncology department at TUSM and member of the biochemistry and genetics program faculties at Sackler.

“Now that we have seen that this approach prevents mammary tumor formation, we would like to see if inhibition of cyclin D1 slows or reverses the growth of existing tumors. We predict that targeting cyclin D1 would diminish the progenitor cells that drive luminal-like tumor growth,” continued Hinds.

“If we find that inhibition of cyclin D1 activity combats existing tumors, the protein may serve as a new target for breast cancer drugs,” said Kuperwasser.

Kuperwasser, based at TUSM and Sackler, and Hinds are also both members of the Molecular Oncology Research Institute (MORI) at Tufts Medical Center and the models in development and cancer program at the Tufts Medical Center Cancer Center.

The first authors are Rinath Jeselsohn, MD, a former fellow in hematology/oncology at Tufts Medical Center; and Nelson Brown, MD, PhD, research fellow at MORI and instructor of medicine at Tufts Medical Center. Additional authors are Lisa Arendt, PhD, DVM, senior research associate in the department of anatomy and cellular biology at TUSM; Ina Klebba, senior research assistant in the department of anatomy and cellular biology at TUSM; and Miaofen Hu, MD, PhD, fellow in the Hinds Laboratory at MORI and also an instructor of medicine at Tufts Medical Center.

This study was funded by grants from the National Cancer Institute and the National Center for Research Resources, both parts of the National Institutes of Health; and The Breast Cancer Research Foundation.

Jeselsohn R, Brown NE, Arendt L, Klebba I, Hu MG, Kuperwasser C, Hinds PW. Cancer Cell. 2010 (January 19); 17: 65-76. “Cyclin D1 Kinase Activity Is Required for the Self-Renewal of Mammary Stem and Progenitor Cells that Are Targets of MMTV-ErbB2 Tumorigenesis.” Published online January 19, 2010, doi: 10.1016/j.ccr.2009.11.024

About Tufts University School of Medicine and the Sackler School of Graduate Biomedical Sciences

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Exposure to Young Triggers New Neuron Creation in Females Exhibiting Maternal Behavior

Thu, 17 Dec 2009 00:00:00 -0500

North Grafton, Mass. (December 17, 2009) – Maternal behavior itself can trigger the development of new neurons in the maternal brain independent of whether the female was pregnant or has nursed, according to a study released by researchers at Tufts University’s Cummings School of Veterinary Medicine. These findings performed in adult, virgin rats were published in Brain Research Bulletin and are available online.

In the study, virgin, or nulliparous, rats were exposed to foster pups each day until they began to exhibit maternal behavior, including crouching over the young, grouping them, or retrieving them back to the nest. Data from the study showed that the nulliparous rats exposed to pups have increased numbers of new neurons.

The research was undertaken by Cummings School Department of Biomedical Sciences researchers Miyako Furuta and Robert Bridges, who is the head of the Cummings School’s reproduction and neurobiology section. Dr. Bridges is also a faculty member in the Neuroscience Program at the Sackler School of Graduate Biomedical Sciences.

Previous research has found that exposure to young can stimulate maternal behavior not only in rats, but also mice, hamsters, monkeys, and even humans. Increased creation of new neurons, or neurogenesis, has also been shown during pregnancy and lactation in rodents and associated with maternal behavior, but studies analyzing neurogenesis in nulliparous animals exhibiting maternal behavior had not been done. The area of the brain that was the focus of the present study was the subventricular region— a region involved in the production of cells that affect odor recognition and possibly recognition of young. Bridges and Furuta found increased numbers of new neurons in the subventricular zone in adult, nulliparous rats that behaved maternally compared with numbers in subjects that either were not exposed to young or exposed to young, but did not behave maternally.

What stimulates increased new neuron production in the nulliparous mothers is not known. One possibility is that the hormone prolactin, which stimulates both the onset of maternal behavior as well as production of neurons during pregnancy, may play a role in the production of new neurons in nulliparous females exhibiting maternal behavior. However, this possibility remains to be investigated. A second possibility is that stimulation received from the young themselves may, in fact, play a crucial role in stimulating maternal neuron production.

“As with all scientific studies, these findings trigger more questions than answers,” said Dr. Robert Bridges, section head of reproduction and neurobiology at Tufts University’s Cummings School of Veterinary Medicine. “Next, we hope to determine what role this neurogenesis plays in terms of the female's behavior and physiological processes. Where do these new cells migrate to within the brain and what do they do? For example, do they affect how a female subsequently perceives her young through recognition of baby odors? These are the questions we hope to answer.”

The study was funded by a National Institutes of Health grant.

In addition to clinical research, the Cummings School of Veterinary Medicine at Tufts University receives National Institutes of Health funding for basic science research in four major areas: Bridges’ reproduction and neurobiology section, infectious diseases, pulmonology, and liver/gastrointestinal function. For more information, please visit the Cummings research page.

About the Cummings School of Veterinary Medicine at Tufts University

Founded in 1978 in North Grafton, Mass., Cummings School of Veterinary Medicine at Tufts University is internationally esteemed for academic programs that impact society and the practice of veterinary medicine; three hospitals and two clinics that combined treat more than 80,000 animals each year; and groundbreaking research that benefits animal, public, and environmental health.

About the Sackler School of Graduate Biomedical Sciences

Tufts Sackler School of Graduate Biomedical Sciences at Tufts University is an international leader in innovative medical education and advanced research. The Sackler School is renowned for excellence in education in basic and clinical research at the cellular and molecular level, and undertakes research that is consistently rated among the highest in the nation for its impact on the advancement of medical science.

About Tufts University

Tufts University, located on three Massachusetts campuses in Boston, Medford/Somerville, and Grafton, and in Talloires, France, is recognized among the premier research universities in the United States. Tufts enjoys a global reputation for academic excellence and for the preparation of students as leaders in a wide range of professions. A growing number of innovative teaching and research initiatives span all Tufts campuses, and collaboration among the faculty and students in the undergraduate, graduate and professional programs across the university's schools is widely encouraged.

Low Cholesterol Transfer Protein Activity Associated with Heart Disease Risk

Tue, 15 Dec 2009 00:00:00 -0500

BOSTON (December 15, 2009) – Although seen as a potential heart disease therapy, raising high-density lipoprotein (HDL) cholesterol levels by inhibiting activity of a transfer protein may not be effective, a new study suggests. Scientists at the Jean Mayer USDA Human Nutrition Research Center on Aging (USDA HNRCA) at Tufts University and Boston University School of Medicine found an association between low plasma cholesterol ester transfer protein (CETP) activity and increased risk of heart disease in the Framingham Heart Study population.

CETP is a protein that shuttles cholesterol throughout the body, thus controlling the levels of HDL, low-density lipoprotein (LDL), and very-low-density lipoprotein (VLDL) in the blood. “Our findings differ from studies suggesting that inhibiting CETP activity would bring a cardiovascular benefit by raising HDL, the so-called good cholesterol credited with lowering the risk of heart disease,” says senior author Jose Ordovas, PhD, director of the Nutritional Genomics Laboratory at the USDA HNRCA. “In a clinical trial testing that hypothesis, heart disease unexpectedly advanced in a surprising number of participants.”
Based on those results, Ordovas and colleagues examined CETP activity in 1,978 Caucasian men and women with a mean age of 51 years and no history of heart disease. They analyzed 15 to 18 years of study visits looking for first cardiac events including heart failure, heart attack, angina, stroke and peripheral vascular disease.

“By the end of the follow-up period, 320 men and women had experienced their first cardiac event,” says Ordovas who is also a professor at the Friedman School of Nutrition Science and Policy at Tufts University. “Participants with low CETP activity were 18 percent more likely to develop cardiovascular disease than people with CETP activity above the median.”

A more in-depth investigation of models eliminated the possibility that age, sex and common risk factors such as smoking, weight, diabetes, and cholesterol levels interfered with the findings. The results are published in the December 15 issue of Circulation.

The authors stress the preliminary nature of their data. “The relationship between CETP activity and HDL levels carries many unknowns, including the influence of genetics,” Ordovas says, pointing to studies of some Japanese families. “Despite very low levels of CETP activities, they still have high heart disease risk. Other genetic studies question the inhibition of CETP, but there is not enough research to discount the possibility that raising HDL levels through CETP inhibitors may reduce the risk of heart disease,” he adds.

This study was funded by the National Heart, Lung and Blood Institute’s Framingham Heart Study and the U.S. Department of Agriculture’s Agricultural Research Service.

Ramachandran S. Vachon,,Michael J. Pencina, Sander J. Robins, Justin P. Zachariah, Guneet Kaur, Ralph B. D'Agostino, and Jose M. Ordovas . “Association of Circulating Cholesteryl Ester Transfer Protein Activity With Incidence of Cardiovascular Disease in the Community” Circulation. 2009;120:2414-2420; published online before print November 30 2009.

About Tufts University School of Nutrition and the Sackler School of Graduate Biomedical Sciences

The Gerald J. and Dorothy R. Friedman School of Nutrition Science and Policy at Tufts University is the only independent school of nutrition in the United States. The school's eight centers, which focus on questions relating to famine, hunger, poverty, and communications, are renowned for the application of scientific research to national and international policy. For two decades, the Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University has studied the relationship between good nutrition and good health in aging populations. Tufts research scientists work with federal agencies to establish the USDA Dietary Guidelines, the Dietary Reference Intakes, and other significant public policies.

Tufts University School of Medicine and the Sackler School of Graduate Biomedical Sciences at Tufts University are international leaders in innovative medical education and advanced research. The School of Medicine and the Sackler School are renowned for excellence in education in general medicine, special combined degree programs in business, health management, public health, bioengineering, and international relations, as well as basic and clinical research at the cellular and molecular level. Ranked among the top in the nation, the School of Medicine is affiliated with six major teaching hospitals and more than 30 health-care facilities. The Sackler School undertakes research that is consistently rated among the highest in the nation for its effect on the advancement of medical science.

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If you are a member of the media interested in learning more about this topic, or speaking with a faculty member at the Friedman School of Nutrition Science and Policy at Tufts University, or another Tufts health sciences researcher, please contact Andrea Grossman at 617-636-3728 or Christine Fennelly at 617-636-3707.

Parasite Evades Death by Promoting Host Cell Survival

Tue, 08 Dec 2009 00:00:00 -0500

BOSTON (December 8, 2009) — The parasite Trypanosoma cruzi (or T. cruzi), which causes Chagas’ disease, will go to great lengths to evade death once it has infected human host cells, researchers have discovered. In a study published in the November 17 online issue of Science Signaling, the researchers describe how a protein called parasite-derived neurotrophic factor (PDNF) prolongs the life of the T. cruzi parasite by activating anti-apoptotic (or anti-cell-death) molecules in the host cell. These protective mechanisms help to explain how host cells continue to survive despite being exploited by T. cruzi parasites.

“We asked ourselves, ‘How is it possible that the host cells stay alive for so long with thousands of T. cruzi parasites consuming the host cell’s vital resources?’ We discovered that PDNF on the surface of the T. cruzi parasite essentially inhibits cell death signals and activates cell-protective mechanisms, ensuring T. cruzi sufficient time to develop and reproduce in the host cell,” says senior author Mercio Perrin, MD, PhD, professor in the Pathology Department at Tufts University School of Medicine (TUSM) and member of the Immunology Program faculty at the Sackler School of Graduate Biomedical Sciences at Tufts.

Taking a multi-faceted approach, the researchers used bioinformatics, immunochemistry, intracellular colocalization microscopy, and in vitro enzymatic techniques to study T. cruzi’s survival in the host. Perrin and co-author Marina Chuenkova, PhD, a research instructor in the pathology department at TUSM and the Sackler School, demonstrated that PDNF is a substrate and activator of Akt kinase, an enzyme that promotes cell survival by inhibiting “cell death” proteins.

“Further investigation showed that within T. cruzi-infected cells, PDNF also activates increased production of Akt, prolonging its protective effects,” says Chuenkova. “Akt is a key regulator of diverse cellular processes, and supports cell survival not only by inhibiting apoptotic molecules, but additionally by increasing nutrient uptake and metabolism,” she continued.

“In short, the T. cruzi parasite has a means of establishing life insurance once it has invaded the host. If we can fully understand the mechanisms behind this protection, we can begin to explore ways to undermine it with treatment,” said Perrin.

Chagas’ disease, typically transmitted to humans by blood-feeding insects, infects an estimated 8 to 11 million people throughout Mexico, and Central and South America. Although it is still rare in the United States, according to the Centers for Disease Control and Prevention (CDC), there are 300,000 people with Chagas’ disease living in the United States, most of whom acquired the disease while living in other countries.

The acute phase of Chagas’ disease can result in fever or swelling at the site of the insect bite, but many people do not experience symptoms at all. If left untreated, the disease enters an indeterminate phase in which no symptoms are present. During this phase, many people are not aware that they are infected, but approximately 30 percent will eventually develop life-threatening complications of the disease, including enlargement of the digestive tract and/or heart.

This study was funded by grants from the National Institute of Neurological Disorders and Stroke (NINDS), a part of the National Institutes of Health.

Chuenkova MV and PereiraPerrin M. Science Signaling. 2009. (November 17); 2(97), ra74. “Trypanosoma cruzi targets Akt in host cells as an intracellular antiapoptotic strategy.” Published online November 17, 2009, doi: 10.1126/scisignal.2000374

About Tufts University School of Medicine and the Sackler School of Graduate Biomedical Sciences

Tufts University School of Medicine and the Sackler School of Graduate Biomedical Sciences at Tufts University are international leaders in innovative medical education and advanced research. The School of Medicine and the Sackler School are renowned for excellence in education in general medicine, special combined degree programs in business, health management, public health, bioengineering and international relations, as well as basic and clinical research at the cellular and molecular level. Ranked among the top in the nation, the School of Medicine is affiliated with six major teaching hospitals and more than 30 health care facilities. The Sackler School undertakes research that is consistently rated among the highest in the nation for its impact on the advancement of medical science.

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