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.
These experiments will advance the current understanding of endocytic machinery and insulin secretion in pancreatic beta cells. By illuminating a fundamental mechanism of membrane trafficking in beta cells, these studies will shed light on new strategies of therapy and potential drug targeting to cure diabetes. In addition, we expect that these studies will have a broad medical relevance beyond the field of diabetes, given the critical role of endocytic membrane trafficking in a wide variety of human diseases.
|Ji, Chen; Fan, Fan; Lou, Xuelin (2017) Vesicle Docking Is a Key Target of Local PI(4,5)P2 Metabolism in the Secretory Pathway of INS-1 Cells. Cell Rep 20:1409-1421|
|Mahapatra, Satyajit; Lou, Xuelin (2017) Dynamin-1 deletion enhances post-tetanic potentiation and quantal size after tetanic stimulation at the calyx of Held. J Physiol 595:193-206|
|Ji, Chen; Lou, Xuelin (2016) Single-molecule Super-resolution Imaging of Phosphatidylinositol 4,5-bisphosphate in the Plasma Membrane with Novel Fluorescent Probes. J Vis Exp :|
|Fan, Fan; Funk, Laura; Lou, Xuelin (2016) Dynamin 1- and 3-Mediated Endocytosis Is Essential for the Development of a Large Central Synapse In Vivo. J Neurosci 36:6097-115|
|Mahapatra, Satyajit; Fan, Fan; Lou, Xuelin (2016) Tissue-specific dynamin-1 deletion at the calyx of Held decreases short-term depression through a mechanism distinct from vesicle resupply. Proc Natl Acad Sci U S A 113:E3150-8|
|Fan, Fan; Ji, Chen; Wu, Yumei et al. (2015) Dynamin 2 regulates biphasic insulin secretion and plasma glucose homeostasis. J Clin Invest 125:4026-41|
|Ji, Chen; Zhang, Yongdeng; Xu, Pingyong et al. (2015) Nanoscale Landscape of Phosphoinositides Revealed by Specific Pleckstrin Homology (PH) Domains Using Single-molecule Superresolution Imaging in the Plasma Membrane. J Biol Chem 290:26978-93|
|Lou, Xuelin; Fan, Fan; Messa, Mirko et al. (2012) Reduced release probability prevents vesicle depletion and transmission failure at dynamin mutant synapses. Proc Natl Acad Sci U S A 109:E515-23|