Characterization of a new model of diabetic retinopathy
Diabetic retinopathy (DR) is a major, common, and specific manifestation of diabetes, that has been estimated to be present in 86% of T1D patients. Approximately half of affected patients (42% off all T1D patients), will have vision-threatening retinopathy. The lack of a good model of this microvascular complication has hampered development and testing of effective therapeutics for DR. We present exciting preliminary data that the BTBR ob/ob murine model of Type II diabetes may develop a proliferative microvascular retinopathy, concurrently with other retinal and microvascular complications of diabetes. The development of diabetes and diabetic complications in this model is the consequence of a genetic mutation resulting in leptin deficiency. Leptin replacement in these mice has been demonstrated by us to effect the reversal of diabetes and, in the case of the kidney, reverse the functional and structural manifestations of advanced diabetic nephropathy. Whether such a dramatic reversal of DR can also be achieved is unknown. We have been exploring the possibility of adapting a new imaging technology (OMAG) for studies of diabetic complications of microvascular origin that can allow investigators to follow the development of DR lesions sequentially over time in the living mouse. Building on these advances in diabetic model development, we propose the following specific aims: Specific Aim #1: To characterize a new mouse model of diabetic retinopathy (DR) and to test the potential for reversal of DR by maneuvers previously shown to reverse diabetic nephropathy in the BTBR ob/ob mouse model of Type 2 Diabetes.Specific Aim #2: to establish a new and non-invasive imaging approach for monitoring and quantitating the development of DR and its potential reversal in the live animal setting, that is directly relevant to the management of humans with DR or at risk to develop DR. Establishing a robust model of DR will enable us and others to better test therapies of potential benefit to humans with DR or at risk for DR in a preclinical setting, and will enable focused studies of the pathogenesis of DR and identify pathophysiologic pathways that result in progression or regression of this lesion.

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