Regulated exocytosis and endocytosis coupling in pancreatic endocrine cells

描述（由申请人提供）：该项目的长期目标是提高我们对β细胞生物学的了解，并探索治疗糖尿病的新治疗策略和潜在的药物靶向。 β细胞对于胰岛素分泌和葡萄糖稳态至关重要。 β细胞功能障碍是糖尿病发展的关键一步。最近的全基因组筛选发现了许多与β细胞中胰岛素颗粒膜运输相关的基因。胞吞作用是与胰岛素胞吐作用相结合的膜运输的基本步骤。虽然及时回收胞吐作用期间添加到细胞表面的膜和囊泡蛋白对于β细胞的结构和功能至关重要，但潜在的分子机制仍未解决。 Dynamin 是内吞机制的保守蛋白，被认为在多种形式的内吞作用中充当夹切酶。然而，最近的遗传学研究对大脑动力功能的经典观点提出了许多新问题。不同的动力亚型可能具有不同或冗余的功能。我们的初步数据表明，胰岛中表达了不止一种亚型，培养物中动力的消融表明膜运输受损。 Dynamin 可能在葡萄糖稳态、糖耐量受损和糖尿病中发挥重要作用。在我们最近对大脑动力的研究和胰岛目前的初步数据的指导下，我们将研究不同动力异构体在内吞作用、胰岛素分泌和葡萄糖稳态调节中的作用。我们将使用生成β细胞特异性、可诱导动力消融β细胞和小鼠模型来进行实时电容测量、荧光成像。

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.