Mitochondrial Cytoprotection to Prevent Islet Cell Death

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DESCRIPTION (provided by applicant): There is considerable amount of evidence indicating that chronic elevation of plasma glucose causes many of the major complications of diabetes, including nephropathy, retinopathy, neuropathy and macro- and microvascular damage. However, the regulation of systemic blood glucose with exogenous insulin is unpredictable at best and patients attempting to abide intensive glucose control are at increased risk for the development of life threatening hypoglycemia. Therefore, the goal of euglycemic maintenance, without the surgical risks conferred by pancreas transplant, is best achieved by islet transplantation. Insulin independence following islet transplant is often attainable only after the infusion of islets derived from two to three donor pancreata and islet cell demise due to apoptosis is a major contributor to the diminished success of single donor islet cell transplants. The multiple donor requirements worsen the existing disparity between organ supply and demand and present a formidable challenge to the clinical translation of islet transplantation as a treatment for type 1 diabetes. SS-31 (d-Arg-Dmt-Lys-Phe-NH2) is a novel cell permeable anti-oxidant peptide that concentrates at high levels at the inner mitochondria! membrane. The SS-31 peptide was recently shown to inhibit mitochondrial swelling and oxidative cell death of neuronal cells. Our studies with mouse islet cells suggest that mitochondrial targeting with SS-31 results in: (1) an increase in islet yield from the pancreas; (2) reduces islet cell apoptosis; and (3) improves post transplant function in diabetic mice. The proposed experiments, to be carried out over a 5-year period, are designed to resolve issues in pancreas retrieval, preservation, islet isolation and transplantation that promote cellular injury culminating in islet cell death. We will evaluate the efficacy of SS-31 to facilitate islet graft survival in a systematic fashion, by examining its effect when administered to islet donors (Specific aim 1), to islet isolation reagents (Specific aim 2), to in-vitro culture (Specific aim 3) and to islet transplant recipients (Specific aim 4). We will examine SS-31 effects (1) islet cell yield, (2) islet cell apoptosis (3) islet mitochondrial function and (4) post transplant islet graft function. It is our expectation that as a result of our systematic investigation, we will gain knowledge translatable to the clinical islet transplantation trials in patients with type 1 diabetes.