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药物靶向。β细胞对于胰岛素分泌和葡萄糖稳态是必不可少的。β细胞功能障碍是糖尿病发展的关键步骤。最近的全基因组筛选确定了许多与β细胞中胰岛素颗粒膜运输相关的基因。内吞作用是与胰岛素胞吐作用相结合的膜运输的基本步骤。虽然在胞吐过程中添加到细胞表面的膜和囊泡蛋白的这种及时检索对于β细胞结构和功能至关重要，但潜在的分子机制仍未得到解决。发动蛋白是内吞机制中的一种保守蛋白，被认为在多种形式的内吞作用中起着钉扎作用。然而，最近的遗传学研究提出了许多新的问题的经典观点的动力蛋白在大脑中的功能。不同的发动蛋白亚型可能具有不同的或冗余的功能。我们的初步数据表明，一个以上的异构体表达在胰岛，消融动力蛋白在文化中表现出受损的膜运输。动力蛋白可能在葡萄糖稳态、糖耐量异常和糖尿病中起重要作用。在我们最近对大脑中动力蛋白的研究和目前胰岛中的初步数据的指导下，我们将研究不同动力蛋白亚型在内吞作用、胰岛素分泌和葡萄糖稳态调节中的作用。我们将进行实时电容测量，荧光成像，使用产生β细胞特异性，诱导发动蛋白消融β细胞和小鼠模型。

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.