Diabetes is characterized by a relative deficiency of insulin. Though islet transplantation is a physiological alternative to exogenous insulin, donor islet shortage and the necessity of lifetime immunosupression limit its application. Inducing endogenous islet neogenesis would circumvent these problems. This has been attempted in diabetic mice by delivering Pdx1, an early transcription factor in pancreatic differentiation, to the liver. Though insulin secreting cells were seen, this was limited by lack of islet formation and hepatic side effects. A significant advance was made when Neurod1, a more down-stream transcription factor, was used. This was effective in reversing the diabetic state while inducing islet-like clusters in the liver. However, as these clusters were immature, there remains a need for better strategies to induce islet neogenesis. Neurogenin3 (Ngn3) is the transcription factor that initiates the differentiation pathway of the endocrine pancreas and thus is an excellent candidate for inducing mature islets. As shown by our preliminary studies, ectopic expression of Ngn3 not only reverses hyperglycemia in diabetic mice but also restores normal glucose tolerance. The goals of this proposal are to establish that ectopic expression of Ngn3 can reverse diabetes and restore glucose tolerance and to delineate the mechanisms by which Ngn3 expression induces islet neogenesis. Our studies will be directed at the following specific aims: 1) to reverse diabetes in insulin deficient diabetic mice by delivering Ngn3 as a transgene, 2) to localize and isolate the induced ectopic islets, characterize their glucose responsiveness and compare them with normal pancreatic islets and 3) to determine the 'cell-of-origin' of these ectopic islets and characterize the islet differentiation program. My clinical & research training in Diabetes at Joslin Diabetes Center and Harvard Medical School, along with my research experience as a fellow in Molecular Medicine at Baylor College of Medicine provide me with a unique perspective to explore the therapeutic potential of islet neogenesis as a viable therapy for diabetes. The mentoring support of Professor Lawrence Chan and the academic environment of Baylor College of Medicine provide me with an excellent opportunity to continue my investigation into molecular therapeutics of diabetes and further develop my skills to attain my goal of being an independent investigator.
