Mechanisms to Induce Islet Proliferation

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DESCRIPTION (provided by applicant): Glucose homeostasis is primarily maintained by the intricate balance of the glucoregulatory, pancreatic hormones insulin and glucagon. Type 1 diabetes mellitus results from the autoimmune destruction of pancreatic beta cells which produce insulin. Currently, the only available cure for type 1 diabetes is pancreatic or islet transplantation. A primary limitation of these bona fide cures is the limited availability of pancreata and pancreatic islets from cadaver donors. Because of this bottleneck, much work has been performed with the goal of finding an alternative source of insulin-producing cells as well as establishing methods to stimulate proliferation of islets harvested for transplantation. The current application addresses the critical need to establish methods to increase pancreatic islet mass. If successful, more patients with type 1 diabetes will benefit from islet transplantation and be free from this serious disease. We have recently discovered that the protease-resistant peptide trefoil factor 3 (TFF3) is a growth factor for pancreatic islets. Since the discovery of TFF3's ability to increase cell proliferation of pancreatic beta cells, we have begun to uncover the signaling pathways that lead to this beneficial effect. However, much work remains to fully characterize these pathways and to perhaps reveal other pathways that can be exploited in order to increase pancreatic beta cell mass. Further, it is equally important to continue to identify novel factors that have the ability to increase beta cell mass. In pursuit of these goals, the following specific aims are proposed: 1) to determine the role of EGF receptor signaling on TFF-3 induced beta cell proliferation, 2) to determine the role of Gene 33/Mig-6/RALT in modulating EGF receptor signaling and beta cell proliferation, and 3) to identify novel factors that regulate pancreatic beta cell mass. In addition to the proposed, scientific specific aims, an equally important aim of this proposal is to continue down the pathway of becoming an independent investigator. This award will be an instrumental component towards my ultimate goal of pursuing a career in diabetes research.