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Neuroligins and Neuroligin-Neurexin Interactions in Islet Beta Cell Function

Neuroligins 和 Neuroligin-Neurexin 在胰岛 β 细胞功能中的相互作用

基本信息

批准号：
8656199
负责人：
STEVEN D CHESSLER
金额：
$ 31.65万
依托单位：
UNIVERSITY OF CALIFORNIA-IRVINE
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-06-10 至 2016-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8656199
关键词：
Adhesions Area Automobile Driving Beta Cell Binding Biology Brain Calcium Calcium Channel Cell Adhesion Molecules Cell Culture Techniques Cell Differentiation process Cell Surface Proteins Cell membrane Cell physiology Cell surface Cells Coculture Techniques Collaborations Data Development Diabetes Mellitus Endocrinology Engineering Environment Ephrins Epidemic Exocytosis Extracellular Protein Family Functional disorder Funding Generations Glucose Goals Health Hyperglycemia Immunoprecipitation Insulin Integral Membrane Protein Islet Cell Knockout Mice Knowledge Laboratories Light Maintenance Mediating Metabolism Methods Modeling Molecular Monitor Natural regeneration Neuraxis Neurobiology Neurons Neurosciences Research Neurotransmitters Non-Insulin-Dependent Diabetes Mellitus Outcome Pancreas Paracrine Communication Pathogenesis Pharmacologic Substance Physiological Play Protein Isoforms Proteins RNA Interference Rattus Regulation Relative (related person)Replacement Therapy Research Research Personnel Role Scaffolding Protein Secretory Cell Synapses Synaptic Cleft Testing Ursidae Family Work base beta cell replacement design diabetes mellitus therapy extracellular gain of function innovation insight insulin secretion interest islet multidisciplinary neurotransmission new therapeutic target novel pancreatic islet function relating to nervous system research study stem synaptic function synaptogenesis therapy development type I and type II diabetes

项目摘要

DESCRIPTION (provided by applicant): The development of glucose-responsive, insulin-secreting cells for beta cell replacement therapy will require a better understanding of the molecular determinants of pancreatic islet function and beta-cell differentiation. Increased knowledge of the mechanisms that mediate insulin secretion is also necessary for the identification of new pharmaceutical targets for the treatment of type 2 diabetes. Guiding this proposal is the long-term goal of determining the role of neuronal synaptic proteins and neurotransmitter mechanisms in insulin secretion, in ¿-cell paracrine signaling, and in the coordination of islet activity. The objective of the present application is to identify the role in beta-cell function of a distinct subset of synaptic cell-surface adhesion molecules: those capable of inducing synapse formation and assembly of the machinery necessary for inhibitory or excitatory neurotransmission. Guided by novel preliminary data, this application focuses on two key families of these adhesion proteins, the neuroligins and their major binding partners, the neurexins. The central hypothesis is that extracellular interactions between neuroligins and neurexins help drive ¿-cell functional maturation, including assembly of the exocytic machinery, and are responsible for the enhancement of insulin secretion induced by ¿-cell-¿ cell contact. To attain the objective of this application, three specific aims are pursued: 1) Identify the neuroligin and neurexin isoforms that are necessary for normal beta-cell secretory function and their role in insulin exocytosis; 2) Identify the mechanisms whereby the neuroligins and neurexins influence beta-cell function; and 3) Test the role of changes in neuroligin and neurexin expression in type 2 diabetes-associated beta-cell dysfunction. Existing neuroligin knockout mice and RNA interference will be used to assess the effect on insulin secretion of reduced expression of neuroligin and neurexin isoforms. The role of neuroligins and neuroligin-neurexin interactions in ¿-cell function will be analyzed using cocultures of INS-1 and dissociated rat-islet cells with neuroligin-expressing HEK293 cells, by immunohistochemical and immunoprecipitation experiments, and by use islet perifusion and monitoring of intracellular calcium. INS-1 cells cultured under glucotoxic conditions and islets from Zucker diabetes fatty rats will be used as models of beta cell dysfunction in type 2 diabetes. The proposed work is innovative because it stems from the novel observation that neuroligins and neurexins are coexpressed on the ¿ cell surface and influence insulin secretion and because it will be carried out in collaboration with a laboratory that is a leader in the field of synaptic function. The proposed research is significant because it is expected to advance and expand our understanding of the role of synaptic cell-surface molecules and extracellular protein interactions in insulin secretion and ¿-cell functional maturation.

描述（由申请人提供）：开发用于 β 细胞替代疗法的葡萄糖反应性胰岛素分泌细胞将需要更好地了解胰岛功能和 β 细胞分化的分子决定因素。增加对介导胰岛素分泌机制的了解对于确定治疗 2 型糖尿病的新药物靶点也是必要的。指导这一提议的长期目标是确定神经元突触蛋白和神经递质机制在胰岛素分泌、细胞旁分泌信号传导和胰岛活动协调中的作用。本申请的目的是确定突触细胞表面粘附分子的独特子集在β细胞功能中的作用：那些能够诱导突触形成和抑制性或兴奋性神经传递所需的机器组装的分子。在新的初步数据的指导下，本申请重点关注这些粘附蛋白的两个关键家族：神经连接蛋白及其主要结合伴侣神经毒素。中心假设是神经连接蛋白和神经毒素之间的细胞外相互作用有助于驱动“细胞”功能成熟，包括胞吐机制的组装，并负责“细胞-”细胞接触诱导的胰岛素分泌的增强。为了实现本申请的目标，我们追求三个具体目标： 1) 鉴定正常 β 细胞分泌功能所必需的神经肽和神经肽亚型及其在胰岛素胞吐作用中的作用； 2) 确定神经连接蛋白和神经毒素影响 β 细胞功能的机制； 3) 测试 Neuroligin 和 neurexin 表达的变化在 2 型糖尿病相关的 β 细胞功能障碍中的作用。现有的 Neuroligin 敲除小鼠和 RNA 干扰将用于评估 Neuroligin 和 neurexin 亚型表达减少对胰岛素分泌的影响。将使用 INS-1 和离解的大鼠胰岛细胞与表达 Neuroligin 的 HEK293 细胞共培养，通过免疫组织化学和免疫沉淀实验，并通过使用胰岛灌注和监测细胞内钙，分析 Neuroligin 和 Neuroligin-neurexin 相互作用在 ¿ 细胞功能中的作用。在糖毒性条件下培养的 INS-1 细胞和来自 Zucker 糖尿病脂肪大鼠的胰岛将被用作 2 型糖尿病中 β 细胞功能障碍的模型。拟议的工作具有创新性，因为它源于神经连接蛋白和神经毒素在细胞表面共表达并影响胰岛素分泌的新观察，并且因为它将与突触功能领域的领先实验室合作进行。拟议的研究意义重大，因为它有望推进和扩大我们对突触细胞表面分子和细胞外蛋白质相互作用在胰岛素分泌和细胞功能成熟中的作用的理解。

项目成果

期刊论文数量（6）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Transcellular neuroligin-2 interactions enhance insulin secretion and are integral to pancreatic β cell function.

跨细胞的neuroligin-2 相互作用增强胰岛素分泌，是胰腺β 细胞功能不可或缺的一部分。

DOI：
10.1074/jbc.m111.280537
发表时间：
2012
期刊：
The Journal of biological chemistry
影响因子：
0
作者：
Suckow,ArthurT;Zhang,Charles;Egodage,Sonya;Comoletti,Davide;Taylor,Palmer;Miller,MeghanT;Sweet,IanR;Chessler,StevenD
通讯作者：
Chessler,StevenD

Cell-sized lipid vesicles for cell-cell synaptic therapies.

用于细胞间突触治疗的细胞大小的脂质囊泡。