The Role of Acetylation in Diabetic Eye Disease

Medical University Of South Carolina, Charleston SC

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Abstract

? DESCRIPTION (provided by applicant): Diabetic retinopathy (DR) is a leading cause of blindness in the US. One of its current clinical treatments is based on the observation that vascular endothelial growth factor (VEGF) levels are elevated in diabetic patients. VEGF is thought to primarily induce neovascularization, but DR often presents clinically as diabetic macular edema (DME) rather than neovascularization. Using primary fetal human RPE cells, our lab has recently shown that the breakdown of retinal pigment epithelium (RPE) barrier function may play an important role in this process. Our long-term goal is to antagonize DME by pharmacologically modulating the function of the RPE. As a first step toward this goal, we have developed a new rabbit model of DR based on intravitreally administered advanced glycation end products (AGE). AGE are known to be increased in the diabetic eye and through inducing NFkBp65 translocation to the nucleus, they are major upstream regulators of VEGF expression. The preliminary data presented in this application provides evidence that intravitreal injection of AGE inhibit the resorption of subretinal fluid through the RPE, thereby promoting the development of retinal edema. In models of blood-brain-barrier injury, histone deacetylase (HDAC) inhibition by valproic acid is known to be protective of the barrier function; therefore, we have also investigated the role of HDACs in our experimental model of DR. We have found that trichostatin A (TSA), a pan-HDAC inhibitor is able to block a loss of RPE function when challenged with AGE. Based on preliminary results, we have developed the following hypothesis: RPE protein acetylation plays a central role in the development of diabetic macular edema. This hypothesis will be tested using these Specific Aims: Aim 1) Investigate the efficacy of HDAC inhibitors in suppressing RPE barrier dysfunction in a diabetic animal model. The first aim will determine RPE dysfunction in a diabetic rat model, confirming the role of diabetes in RPE functional loss in DME. TSA will be administered to determine if rescue of RPE function in diabetic rats can be achieved. Aim 2) Investigate how HDAC inhibitors modulate AGE-induced changes in RPE barrier function in vitro. The second aim seeks to characterize the signaling pathways responsible for dysfunction of the RPE in DME and rescue of function by TSA. Goal: Discover better treatment for DME which specifically targets the pathobiology of the disease and has a preferential side effect profile. Relevance to Agency: Diabetes has pathological sequelae in many organ systems; however the irreversible damage seen in diabetic macular edema which can ultimately lead to blindness makes it an extremely important target for innovative treatment. This work proposes acetylation regulation as a potential target for treatment of this and other diabetic diseases.