Studies

Diabetic retinopathy, seen here in an fundus photograph and in a cross-sectional diagram, causes blood vessels in the retina to leak fluid or blood and grow branches and scar tissue. This can lead to blurred, distorted vision.

2. DIABETIC RETINOPATHY/NEOVASCULARIZATION

--Anand-Apte Lab
--Personnel: Mariya Ali, Alecia Cutler, Quteba Ebrahem, Bharathi Govindarajan, Jian Hua Qi, Carolyn Ustach and Jing Xie

(a) Choroidal Neovascularization Regulated by Extracellular Matrix Much progress has been made in the field of angiogenesis research, which has been fueled by the hypothesis that inhibition of angiogenesis would be a useful strategy to treat cancers. However, there are a number of other diseases in which pathologic angiogenesis plays a role. Retinal neovascularization involves the development of sprouts from retinal vessels, which usually penetrates the inner limiting membrane (ILM) and grows into the vitreous. Retinal neovascularization is observed in ischaemic retinopathies such as diabetic retinopathy, retinopathy of prematurity, central vein occlusion and branch retinal vein occlusion. Angiogenesis is a multistep process requiring degradation of the basement membrane of the parent vessel, endothelial cell migration, capillary tube formation and endothelial cell proliferation. A precise spatial and temporal regulation of extracellular proteolytic activity appears to be important in this process of neovascularization. The broad, long-term goal of the project is to gain an understanding of the mechanism(s) by which alterations in matrix integrity may regulate retinal neovascularization. We have identified a novel ADAM-TS like molecule that is expressed in RPE cells and may play a role in angiogenesis. We are attempting to identify other novel endogenous inducers and inhibitors of angiogenesis to understand the basic biology of neovascularization and with a final goal of designing therapeutic approaches to combat this process in disease states. Our ultimate goal is the prevention and/or reversal of this process in an effort to control the devastating consequences of choroidal neovascularization.

--deS Senanayake Laboratory
--Personnel: Preenie deS Senanayake, Ph.D.

(c) Role of Retinal Angiotensin II in Diabetic Retinopathy Diabetic retinopathy is a major microvascular complication of diabetes mellitus, producing visual impairment that often results in blindness. Although angiotensin appears to be produced in the retina, and we found that its expression is changed by increasing blood pressure in animals, we must determine if the retina is actually a target tissue for this peptide. The influence of angiotensin on the retina is unexplored to date. Because one of the most successful therapies for hypertension is inhibition of angiotensin, discovering the properties and mechanisms of the retinal renin angiotensin system has immense potential for revealing the mechanisms by which hypertension exacerbates diabetic retinopathy. These studies could indicate whether the retinal renin angiotensin system is likely to be a therapeutic target with far reaching clinical, social and economic consequences.

(d) Angiotensin II and its Receptor Sub-types in Retina and RPE-Choroid Complex The involvement of Angiotensin II (Ang II) in diabetic retinopathy has been implied in several studies, intraocular and serum levels of angiotensin converting enzyme (ACE), prorenin and Ang II have been reported to be correlated with the severity of retinopathy. ACE inhibitors have been reported to improve the blood-brain barrier in diabetic patients and to have a favorable effect on diabetic retinopathy, indicating that the therapeutic benefit is dependent on the inhibition of Ang II formation from Ang I. The reported tissue concentrations of renin are too high to be an accumulation from the circulation. These findings taken together support the concept of an intraocular synthesis of Ang II independent of the circulation in humans. A fundamental requirement for understanding the role of the RAS in diabetic retinopathy and therapeutic targeting of the ocular RAS is the in vivo expression of Ang II peptides and receptors in non-diabetic and diabetic patients. These findings will provide an index of activity of the RAS in the retina and RPE-choroid complex.

(e) Glucose and Glycogen in Diabetic and Normal Retina, RPE and Choroid This project will test the hypothesis that the processing of glucose and glycogen in the diabetic RPE-choroid is significantly different from that of the control RPE-choroid resulting in altered GAG biochemical fine structure.

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