People

Maria Grant, MD

grantma@medicine.ufl.edu

Our research efforts have been focused on characterizing the molecular mechanisms responsible for the development of diabetic retinopathy. Retinopathy is the most frequent microvascular complication of diabetes mellitus and the leading cause of adult blindness in the U.S. We have attempted to understand the role of growth factors, in particular insulin-like growth factor I, in the pathogenesis of aberrant neovascularization that characterizes proliferative diabetic retinopathy. We are using a novel in vitro system of cultured human retinal endothelial cells (HREC) from diabetic and nondiabetic donors to characterize cellular interactions with growth factors.

In addition to growth factors, the extracellular matrix (ECM) is an important regulator of endothelial cell behavior. Increased amounts of aberrant matrix seen in diabetic retinopathy may contribute to the endothelial cell dysfunction found in the disease. We have established a role for the protease inhibitor plasminogen activator inhibitor in regulating ECM accumulation in diabetic retinopathy. We also have examined the effect of matrix protein fibronectin (Fn) and fragments of Fn (Fn-f) in modulating stages of angiogenesis.

Recent studies in our laboratory indicate altered endothelial cell nitric oxide (NO) regulation in diabetic retinal endothelium. We identified increased inducible nitric oxide synthase, enhanced vascular endothelial growth factor levels and disruption of the blood retinal barrier in the retinas of diabetic rats compared to non-diabetic age-matched controls. We are characterizing the relationship between altered NO regulation and integrity of the blood retinal barrier in diabetes and explore the feasibility of strategies designed to maintain blood retinal barrier integrity in animal models of diabetes.

We have also demonstrated that the adenosine A2b receptor is expressed in increased levels in angiogenic blood vessels and is the receptor that mediates adenosine's action on retinal growth factor production. Using in vitro systems, we are examining the mechanism by which adenosine increases vascular endothelial growth factor (VEGF) mRNA expression in HREC cultures. Using an in vivo model, we are testing the efficacy of vector-mediated gene expression of a hypoxia-regulated ribozyme to target adenosine A2b receptor mRNA in mice with oxygen-induced retinopathy and inhibit retinal neovascularization. We are also using chimeric NOD mice with reconstituted bone marrow from green fluorescent protein transgenic mice to elucidate the role of bone marrow-derived angioblasts in the development of ischemic retinal angiogenesis. These studies use our newly developed model of preretinal angiogenesis in adult mice. Results from these studies will generate new information on and evaluate the feasibility of novel therapeutic approaches directed to adenosine A2b inhibition.