alpha-Endosulfine, Insulin,& Adult Tissue Growth Control

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DESCRIPTION (provided by applicant): Little is known about how adult tissues maintained by stem cells sense and respond to external stimuli such as changes in nutrition. We established the Drosophila ovary as a model system in which to study this question. We showed that nutritional status can control the number of cells produced in the Drosophila ovary, and that the insulin pathway and alpha-endosulfine are part of the regulatory machinery. In mammals, alpha-endosulfine is likely to be involved in the regulation of ion channels and in the secretion of insulin; however, the available evidence as to its precise role is conflicting. In pancreatic beta cells in culture, alpha-endosulfine binds to the regulatory subunit, SUR, of a potassium channel, triggering membrane depolarization, calcium influx and secretion of insulin. In other studies, alpha-endosulfine was shown to inhibit insulin secretion by blocking calcium channels. Genetic analyses, which will be crucial in resolving the current controversies and understanding the in vivo role of alpha-endosulfine, have not yet been conducted. We propose a focused set of genetic approaches, combined with biochemical and cell biological assays, to address the role of alpha-endosulfine in tissue growth regulation, and test the hypothesis that it regulates ion channel activity and insulin secretion in vivo. The specific aims are: (1) to determine in what tissue alpha-endosulfine is required and if it is involved in insulin secretion; (2) to determine if alpha-endosulfine acts via the modulation SUR activity; and (3) to investigate the mechanism of regulation of alpha-endosulfine. These approaches will contribute significantly to the understanding of the role of alpha-endosulfine in insulin secretion, as well as of normal biological processes in which insulin is required. In particular, they will help elucidate mechanisms that lead to type n diabetes, an important step towards the development of new drugs to treat this disease. In addition, these studies will provide new insights into how stem cell-supported tissues respond to nutritional changes and, perhaps, identify new ways to manipulate this response for therapeutic purposes.