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Regulated exocytosis and endocytosis coupling in pancreatic endocrine cells

胰腺内分泌细胞中胞吐作用和内吞作用耦合的调节

基本信息

批准号：
8338909
负责人：
Xuelin Lou
金额：
$ 32.03万
依托单位：
UNIVERSITY OF WISCONSIN-MADISON
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-09-30 至 2016-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8338909
关键词：
Ablation Address Affect Animals Antibodies Area Beta Cell Blood Glucose Brain Cell Culture Techniques Cell membrane Cell physiology Cell surface Cells Cellular Structures Cellular biology Coupled Coupling Data Development Diabetes Mellitus Drug Delivery Systems Drug or chemical Tissue Distribution Dynamin Dynamin 2 Dynamin I Dynamin III Electric Capacitance Endocrine Endocytosis Equilibrium Exocytosis Genes Genetic Glucose Goals Golgi Apparatus Guanosine Triphosphate Phosphohydrolases Hormones Human body Image Injection of therapeutic agent Insulin Islets of Langerhans Knock-out Knockout Mice Knowledge Life Light Location Mammals Measurement Measures Mediating Medical Membrane Membrane Protein Traffic Molecular Mus Nature Nerve Pancreas Pathology Plasma Play Polymerase Chain Reaction Protein Family Protein Isoforms Proteins Recycling Regulation Reporting Residual state Rest Retrieval Reverse Transcription Role Science Slice Source Staging Structure of beta Cell of islet Synapses Synaptic Transmission Synaptic Vesicles Tamoxifen Testing Time Transgenic Mice Vesicle Virus Western Blotting Work blood glucose regulation fluorescence imaging genome wide association study human disease imaging modality immunocytochemistry impaired glucose tolerance improved insight insulin granule insulin secretion loss of function mouse model novel strategies patch clamp research study response trafficking

项目摘要

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.

描述(由申请者提供)：这个项目的长期目标是提高我们对β细胞生物学的了解，并探索新的治疗策略和潜在的药物靶向治疗糖尿病。β细胞对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过程中的关键一步。最近的全基因组筛查发现了许多与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转运的基本步骤。尽管这种及时回收胞吐过程中添加到细胞表面的膜和囊泡蛋白对β细胞的结构和功能至关重要，但其潜在的分子机制仍未解决。Dynamin是内吞机制中的一种保守蛋白质，被认为在许多形式的内吞作用中都是一种追逐酶。然而，最近的遗传学研究对大脑中动力素功能的经典观点提出了许多新的问题。不同的动力蛋白亚型可能具有不同的或冗余的功能。我们的初步数据显示，在胰岛表达不止一种异构体，去除培养中的动力素显示膜转运受损。动力蛋白可能在葡萄糖稳态、糖耐量受损和糖尿病中发挥重要作用。根据我们最近对大脑中的动力蛋白的研究和目前胰岛中的初步数据，我们将研究不同的动力蛋白亚型在调节内吞作用、胰岛素分泌和葡萄糖稳态中的作用。我们将使用产生β细胞特异性的、可诱导的动态消融的β细胞和小鼠模型，进行实时电容测量、荧光成像。