The role of tomosyn-2 in insulin secretion

Tomosyn-2在胰岛素分泌中的作用

基本信息

批准号：
8916088
负责人：
Sushant Bhatnagar
金额：
$ 8.72万
依托单位：
UNIVERSITY OF WISCONSIN-MADISON
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-09-01 至 2016-02-14
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8916088
关键词：
Affect Animal Model Animals Area Award Beta Cell Binding Binding Proteins Biochemical Biochemistry Biological Assay Blood Glucose Breeding Cell Line Cell membrane Cell physiology Cells Chromosomes, Human, Pair 16 Code Complex Confocal Microscopy Congenic Mice Congenic Strain Cytoplasmic Granules Defect Development Disease Drug Targeting Epidemic Exocytosis Fasting Gelsolin Generations Genes Genetic Glucose Goals Grant Health Homeostasis Hyperglycemia Hypoglycemia In Vitro Insulin Insulin Resistance Intervention Islets of Langerhans Knockout Mice Laboratories Learning Life Liposomes Maps Mass Spectrum Analysis Membrane Mentors Mouse Strains Mus Mutation Non-Insulin-Dependent Diabetes Mellitus Obesity Open Reading Frames Pancreas Pathway interactions Patients Peripheral Phase Phenotype Phosphorylation Phosphorylation Site Plasma Play Post-Translational Protein Processing Predisposition Protein Kinase C Alpha Proteins Quantitative Trait Loci Regulation Research Risk Role SNAP receptor Signal Pathway Signal Transduction Single Nucleotide Polymorphism Societies Techniques Therapeutic Training Ubiquitination Work career career development design diabetic experience fasting plasma glucose forward genetics genetic regulatory protein insight insulin granule insulin secretion islet member mouse model non-genetic novel peripheral blood prevent protein degradation receptor risk variant secretion process synaptotagmin I syntaxin tool ubiquitin-protein ligase

项目摘要

DESCRIPTION (provided by applicant): Type 2 diabetes (T2D) is reaching epidemic proportions in Western societies. T2D occurs when the ß-cells of the pancreas do not secrete enough insulin to properly regulate peripheral blood glucose levels, usually in the face of obesity and associated peripheral insulin resistance. The mechanisms underlying insulin secretion are not properly understood. Using a forward genetics approach, we have discovered that a single nucleotide polymorphism (SNP) in the protein-coding region of the gene for tomosyn-2 is directly correlated with the hypoinsulinemic/hyperglycemic phenotype. Tomosyn-2 is a relatively uncharacterized protein and the mechanism by which it regulates insulin secretion is not known. The work proposed here in this Pathways to Independence Award application has two primary goals: 1) to elucidate the mechanism by which tomosyn-2 regulates insulin secretion in pancreatic ß-cells, and 2) to use my development of this novel area of T2D research to facilitate the development of my career from the mentored phase to an independent phase. During the mentored phase of the grant, I will receive training in mass spectrometry, in vitro liposome fusion assays, membrane biochemistry, and the generation of the tomosyn-2 knockout mouse. The research conducted in the mentored phase will examine the effect of identified phosphorylation sites on the ability of tomosyn-2 to regulate insulin secretion and to understand the mechanism by which tomosyn-2 is targeted for proteosomal degradation. During the independent phase of the grant, my research will examine the mechanism by which tomosyn-2 inhibits insulin secretion by regulating the activity of soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) proteins and characterize the role of novel tomosyn-2 binding proteins. These studies will provide novel clues to the mechanism by which tomosyn-2 inhibits insulin secretion and will further our understanding of the regulation of insulin secretio in T2D.

描述（通过应用程序提供）：2型糖尿病（T2D）在西方社会中达到流行比例。当胰腺的ß细胞没有足够秘密以适当调节外周血葡萄糖水平时，就会发生T2D 和相关的外周胰岛素抵抗。胰岛素分泌的基础机制尚未正确理解。使用远期遗传学方法，我们发现在tomosyn-2基因的蛋白质编码区域中的单个核丁二醇多态性（SNP）与低胰岛素/高血糖表型直接相关。 Tomosyn-2是一种相对未表征的蛋白质，尚不清楚调节胰岛素分泌的机制。在此通往独立奖的途径中，这里提出的工作有两个主要目标：1）阐明TomoSyn-2调节胰腺β细胞中胰岛素分泌的机制，以及2）使用我对这项T2D研究的发展发展，以支持我的职业生涯从MEDED阶段到独立阶段的发展。在赠款的修改阶段，我将接受质谱，体外脂质体融合测定，膜生物化学和产生Tomosyn-2敲除小鼠的培训。在修补阶段进行的研究将检查已鉴定的磷酸化位点对tomosyn-2调节胰岛素分泌能力并了解tomosyn-2靶向蛋白质体降解的机制的影响。在赠款的独立阶段，我的研究将检查tomosyn-2通过确定固体N-乙基迈雷酰亚胺敏感因子附着蛋白（SNARE）蛋白的活性来抑制胰岛素分泌的机制，并表征了新型Tomosyn-2结合蛋白的作用。这些研究将为Tomosyn-2抑制胰岛素分泌的机制提供新的线索，并将进一步了解T2D中胰岛素秘密的调节。