Developing innovative strategies for anti-ocular angiogenesis therapeutics
In view: our aging population. While enhanced medical care continues to offer newfound opportunities for prolonging life, our global population becomes increasingly ‘at risk’ for many co-morbidities, which arise during aging, including obesity and diabetes. Indeed, there are now over 35 million people in the United States aged over 65; this number is projected to increase by 36% (55 million people) by the year 2020! Perhaps, then, it is not surprising to note that this cohort experiences the highest risk of vision-obliterating ocular diseases. For example, age-related macular degeneration (AMD), affects only 2% of those aged over 50 years, with 30% affected, 75 years and over. And, with over 21 million Americans now suffering with diabetes, there are roughly 175,000 patients diagnosed with diabetic retinopathy (DR) annually. For those suffering with either wet AMD or DR, it is the vascular complications that can ultimately blind patients though a number of different, but related, mechanisms. Whether accompanying wet AMD or DR, these vascular lesions evolve from the uncontrolled growth and invasive behavior of the small blood vessels known as capillaries. The are two major cell types of capillaries: the blood-compatible endothelial cells lining the vessels, and the contractile, smooth muscle-like pericytes that modulate vessel tone and growth. Within these capillaries signals can go awry due to altered genetics or through perturbations in the microenvironmental stimuli within or between these vascular cell types. Whether confounded by altered glycemic control due to diabetes or immune surveillance mechanisms arising from the genetics or ‘epi-genetics’ accompanying or linked to aging, these diseases represent the major cause of adult blindness in the Western society. Therefore, it is imperative that novel therapeutics capable of preventing or reversing vision-altering behavior or blindness that arises from AMD or diabetes be developed and brought into the clinic.
Innovations in ocular anti-angiogenic therapeutics. Jennifer Durham, a Cellular & Molecular Physiology graduate student in Ira Herman’s laboratory and member of the Center for Innovations in Wound Healing Research, Tufts University School of Medicine, is interested in the molecular mechanisms by which uncontrolled blood vessel formation leads to vision loss in AMD and DR. Inspired by those visionary scientists who founded the field of angiogenesis research, i.e. the study of cellular processes by which new blood vessels are generated via sprouting from pre-existing vasculature, she joins those members of the Herman lab and the international scientific community who are studying mechanisms underlying the neovascular pathology and vascular complications accompanying AMD and DR, while developing innovative strategies aimed at anti-ocular angiogenic therapeutics.
Angiogenic intervention: Controlling vascular cell motility and growth. A crucial step that drives the angiogenic cascade is vascular endothelial cell motility or migration. This rate-limiting step, coordinated by a signaling network connected to and through the β-actin cytoskeleton, is controlled via a novel, β-actin filament binding protein, βcap73. Discovered in the Herman laboratory, this molecule’s expression has been demonstrated and linked to defective cell processes, including cell migration. As a result, a central tenet of Jenn’s current work is that controlled over-expression of endothelial cell βcap73 would significantly interfere with or block the migration required for pathologic angiogenesis.
Validation? Jenn’s experiments in cell culture model systems are now paving the way for hypothesis validation in genetically-defined animal models. For example, Jenn created an adenoviral construct bearing the βcap73 gene. After exposure of endothelial cells to this adenoviral construct, βcap73 is expressed at significantly higher levels than would normally occur. As her recently published work reveals [see Durham & Herman, 2009] adenovirus-mediated βcap73 over-expression robustly inhibits angiogenesis via: i) impairing cell migration, ii) antagonizing cell remodeling, and iii) inducing anoikis, a form of programmed cellular death, which emanates as a result of altered cell shape or attachment. Now, Jenn’s studies are aimed at validating these effects in vivo using animals. With assistance from the Tufts transgenic core, Jenn has been able to create several drug-sensitive mouse lines with altered βcap73 genetics, such that upon exposure to a specific drug, these genetically-altered mice will produce high levels of βcap73 specifically in their endothelial cells. Jenn will re-test whether elevated endothelial cell expression of βcap73 will prevent pathologic ocular angiogenesis. If so, then novel anti-ocular angiogenesis therapeutics may be around the corner… we will soon find out!
Read earlier Research Spotlights to Learn More about Exciting Work at the Sackler School.