Glucose is a major energy source for all mammalian cells. In normal animals, blood glucose levels are maintained within a very narrow range. Hormones produced by pancreatic islets including insulin and glucagon play a key role in maintaining blood glucose homeostasis. Recently, urocortin (Ucn) III, a member of the corticotropin releasing factor (CRF) peptide family, was found to be expressed in ( cells in the islet. The proposed project will investigate the function and mechanism of endogenous Ucn III in islet hormone secretion and its role in the regulation of glucose homeostasis. In vitro primary islet cultures will be used to assess the role of endogenous Ucn IN on insulin and glucagon secretion. Transgenic mice with either ( cell Ucn III deletion or overexpression will be generated to examine the function of Ucn III in regulating blood glucose homeostasis. In addition, the role of nutrients and islet hormones on the expression of Ucn III in the pancreas will be examined to substantiate the hypothesis that pancreatic Ucn III in involved in the regulation of glucose homeostasis. Results from this proposed project will provide important insight about the possible role of Ucn III in metabolic disorders such as diabetes. The information may also potentially be used for drug design and therapeutic applications for diabetes. Career Goals: The candidate's long-term career objectives include obtaining a faculty position in a leading research and teaching institution to conduct hormone related research. The applicant received his PhD and initial postdoctoral training on neuroendocrine regulation of feeding and metabolism. The training that the candidate will obtain form the proposed project includes (1) a comprehensive understanding of regulation and function of islet hormones and overall regulation of blood glucose homeostasis, (2) the ability to set up in vitro primary cultures to address specific questions and (3) the ability to generate transgenic mice with either deletion or overexpression of gene of interest in a temporal and spatial manner to investigate the function of the gene encoded product. The additional knowledge and research skills acquired from the application, together with previous background, will enable the applicant to study complicated, multifaceted metabolic disorders such as diabetes mellitus