Regulated exocytosis and endocytosis coupling in pancreatic endocrine cells

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DESCRIPTION (provided by applicant): The long term goal of this project is to improve our knowledge of beta cell biology and to explore new strategies of therapy and potential drug targeting to cure diabetes. Beta cells are essential for insulin secretion and glucose homeostasis. Malfunction of beta cells is a key step in the development of diabetes. Recent genome-wide screening identified numerous genes that associate with insulin granule membrane trafficking in beta cells. Endocytosis is a fundamental step of membrane trafficking that is coupled with insulin exocytosis. While this timely retrieval of membrane and vesicle proteins that are added to the cell surface during exocytosis is critical for beta cell structure and function, the underlying molecular mechanism remains unresolved. Dynamin, a conserved protein of the endocytic machinery, has been thought to serves as a pinchase in many forms of endocytosis. However, recent genetic studies raised many new questions on the classical view of dynamin function in the brain. Different dynamin isoform may have distinct or redundant functions. Our preliminary data demonstrated more than one isoforms expressed in pancreatic islets, ablation of dynamins in culture showed impaired membrane trafficking. Dynamin may play an important role in glucose homeostasis, impaired glucose tolerance and diabetes. Guided by our recent study on dynamin in the brain and current preliminary data in pancreatic islets, we will investigate the role of different dynamin isoforms in regulation of endocytosis, insulin secretion, and glucose homeostasis. We will perform real-time capacitance measurement, fluorescence imaging, using generate beta cell specific, inducible dynamin ablation beta cells and mouse models.