Type I diabetes originates from the autoimmune and inflammatory destruction of insulin-producing pancreatic beta cells, and the ensuing hyperglycemia carries vascular and renal complications with severe morbidity and mortality. Transplantation of pancreatic islets has been considered for the treatment of type I diabetes. Although encouraging results were reported in earlier clinical trials, the achievement of insulin-independence strictly depends on the survival of beta cells in the transplanted graft. Loss of beta cells occurs by excessive apoptosis (or programmed cell death) induced by organ manipulation, inadequate vascularization, multiple cytotoxic signals, and insufficient compensatory proliferation of remaining beta cells. This has prompted the search for """"""""protective genes"""""""" capable of improving islet cell survival. Our laboratory has focused on survivin, a member of the Inhibitor of Apoptosis (lAP) gene family. Much of the survivin pathway has been recently mapped in cancer, where the survivin gene is dramatically up regulated, and mediates suppression of apoptosis (i), preservation of mitotic progression (ii), and maintenance of angiogenesis (iii). We now plan to exploit the survivin pathway for protection of normal tissues, and we hypothesize that its multiple functions may be ideally suited to counteract islet apoptosis, facilitate beta cell proliferation and support neovascularization. In the first specific aim, we will use gene transfer of survivin in pancreatic islets to monitor resistance to caspase-dependent apoptotic pathways, correction of hyperglycemia in transplanted diabetic recipient mice, synergy with immunotherapeutic regimens, and increased neovascular capillary formation. In the second specific aim, we will generate a transgenic mouse with targeted expression of survivin in pancreatic beta cells, and monitor correction of hyperglycemia, preservation of islet mass and enhanced beta cell proliferation in genetic and chemical models of diabetes. The results of these studies may yield a novel strategy to promote long-term acceptance of transplanted pancreatic islets and correction of diabetes.
