Request for Funding

Medical Student Research Fellowship for Summer 2001

Mentor: Nadir Alikacem, Ph.D.

Department: Ophthalmology

Room number: RC 101

Mail Code: 8592

Phone number: (214) 905 - 0872

E-mail: Nadir.Alikacem@UTSouthwestern.edu

Project title: Mechanism of retinal VEGF upregulation in diabetic retinopathy

Human subjects IRB approved project number (where applicable):

Animal subjects IRB approved project number (where applicable): APN # 0823-00-06-1

Project Type (patient-based research, animal-based research, or basic research; this characterization is only to permit a general classification for grouping similar types of projects)        Animal-based research

Brief Description of Project:

Diabetic retinopathy continues to be the leading cause of blindness among the working age population. Although several clinical trials have highlighted the importance of intensive insulin therapy to prevent long-term microvascular complications in type-1 diabetes, they consistently reported serious worsening of retinopathy during the first two-years of the therapy. This worsening was more frequent and more severe when retinopathy was more advanced and diabetes was of longer duration. The underlying mechanisms that cause the initial worsening of retinopathy remain unclear. Vascular endothelial growth factor (VEGF) is a potent angiogenic and permeability-enhancing biological factor. It is secreted by several cell types in the retina. VEGF has been causally linked to many of the changes observed in diabetic retinopathy including retinal edema, ischemia, hemorrhage, and microaneurysm formation in humans as well as in animal models. We demonstrated the potency of VEGF by showing that intravitreal sustained release of VEGF by novel intraocular biodegradable devices led to the breakdown of the blood-retinal barrier followed by retinal neovascularization, hemorrhage and retinal detachment in eyes of normal animals. We hypothesize that the initiation of intensive insulin therapy in hyperglycemic animals increases retinal IGF-1 levels leading to the up-regulation of retinal VEGF expression, which induces breakdown of the blood-retinal barrier. To test this hypothesis, we will use our novel intraocular biodegradable fibers as intraocular delivery devices. The results of these studies will elucidate the underlying mechanisms that lead to the initial worsening of retinopathy in response to intensive insulin therapy. These studies will also establish the effects of strict control of hyperglycemia on retinal VEGF expression. Furthermore, the outcome of our research could lead to the development of new approaches for treatment or prevention of diabetic retinopathy by local sustained delivery of anti-VEGF antibodies or other drugs.

Previous Research Activities or Publications with Medical Students:

Numerous

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