The applicant proposes a program of research and study to prepare for a career in investigation of molecular mechanisms of endocrine disease. The proposed studies are designed to develop research skills in molecular biology, cell biology, and animal models of disease. The phase I research will be a supervised program in which these skills are advanced and a course of didactic study is completed. In phase II, intensive, more independent investigation will be conducted in a mentored environment to address fundamental aspects of insulin gene regulation of relevance to diabetes mellitus. The program will be mentored by Dr. Joel Habener, and a portion of phase II studies will be conducted in collaboration with Dr. Gordon Weir. The molecular mechanisms which control changing levels of insulin gene transcription in response to varying glucose concentrations are inadequately understood. The proposed studies will test the hypothesis that a pancreas- specific transcription factor, IDX-1, is a fundamental and critical regulator of glucose-mediated transcriptional expression of the insulin gene in the beta cells of the endocrine pancreas. Defective regulation of the homeoprotein IDX-1 by prolonged exposure to high levels of glucose may explain the impairment of insulin production characteristically seen in patients with non-insulin-dependent diabetes mellitus. Further, it is proposed that phosphorylation of IDX-1 regulates activation of insulin gene transcription.
The aims of the proposed studies are 1) to identify physiologic signals which regulate IDX-1 phosphorylation, 2) to determine whether IDX-1 phosphorylation alters activation of insulin gene transcription, and 3) to study the effects of IDX-1 inactivation on glucose-mediated regulation of insulin gene transcription. Elucidation of the role of IDX-1 in insulin gene regulation may define molecular mechanisms central to the development of new treatment approaches for diabetic patients.
