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：
8219529
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/8219529
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. PUBLIC HEALTH RELEVANCE: 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.

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，并探索治疗的新策略和潜在的药物靶向治疗糖尿病。 β细胞对于胰岛素分泌和葡萄糖稳态至关重要。 β细胞的故障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。内吞作用是膜运输的基本步骤，与胰岛素胞吐作用相结合。虽然这种及时的膜和囊泡蛋白在胞吞作用过程中被添加到细胞表面的膜和囊泡蛋白对β细胞结构和功能至关重要，但潜在的分子机制仍未解决。 Dynamin是一种保守的内吞机械蛋白，被认为是多种形式内吞作用的施用蛋白。但是，最近的遗传研究提出了许多关于大脑动力蛋白功能的经典观点的新问题。不同的动力素同工型可能具有独特的或冗余的功能。我们的初步数据证明了在胰岛中表达的一种以上的同工型，在培养物中的消融表现出膜运输受损。动力蛋白可能在葡萄糖稳态，葡萄糖耐受性和糖尿病中起重要作用。在我们最近对胰岛胰岛中动力蛋白和当前初步数据的研究的指导下，我们将研究不同动力蛋白同工型在调节内吞作用，胰岛素分泌和葡萄糖稳态中的作用。我们将使用生成β细胞特异性的，诱导的动力蛋白消融β细胞和小鼠模型进行实时电容测量，荧光成像。公共卫生相关性：这些实验将提高胰腺β细胞中对内吞机械和胰岛素分泌的当前理解。通过阐明β细胞中膜运输的基本机制，这些研究将阐明新的治疗策略和潜在的药物靶向治疗糖尿病。此外，鉴于内吞膜运输在各种人类疾病中的关键作用，我们预计这些研究将在糖尿病领域具有广泛的医学相关性。