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：
9411112
负责人：
Sushant Bhatnagar
金额：
$ 24.08万
依托单位：
UNIVERSITY OF ALABAMA AT BIRMINGHAM
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-02-15 至 2019-02-14
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9411112
关键词：
Affect Animal Model Animals Area Award Beta Cell Binding Binding Proteins Biochemical Biochemistry Biological Assay Biophysics Blood Glucose Breeding Cell Line Cell membrane Cell physiology 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 Homeostasis Hyperglycemia Hypoglycemia Impairment In Vitro Insulin Insulin Resistance Intervention Knockout Mice Laboratories Learning Life Liposomes Mass Spectrum Analysis Membrane Mentors Mouse Strains Mus Mutation Non-Insulin-Dependent Diabetes Mellitus Obesity Open Reading Frames PRKCA gene Pathway interactions Patients Peripheral Phase Phenotype Phosphorylation Phosphorylation Site Plasma Play Post-Translational Protein Processing Predisposition Proteins Quantitative Trait Loci Regulation Research Risk Role SNAP receptor Signal Pathway Signal Transduction Single Nucleotide Polymorphism Societies Structure of beta Cell of islet Techniques Therapeutic Training Ubiquitination Work career career development design experience fasting plasma glucose forward genetics genetic approach genetic regulatory protein insight insulin granule insulin secretion islet member mouse model non-genetic novel peripheral blood prevent protein degradation public health relevance receptor risk variant secretion process synaptotagmin syntaxin syntaxin A 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（由申请人提供）：2 型糖尿病 (T2D) 在西方社会中已达到流行程度，当胰腺的 β 细胞不能分泌足够的胰岛素来正确调节外周血糖水平时（通常是在肥胖的情况下），就会发生 T2D。和相关的外周胰岛素抵抗。使用正向遗传学方法，我们发现 tomosyn-2 基因的蛋白质编码区中的单核苷酸多态性 (SNP) 与胰岛素分泌直接相关。 Tomosyn-2 是一种相对未表征的蛋白质，其调节胰岛素分泌的机制尚不清楚，该独立之路奖申请中提出的工作有两个主要内容。目标：1) 阐明 tomosyn-2 调节胰腺 β 细胞胰岛素分泌的机制，2) 利用我在 T2D 研究这一新领域的发展，促进我的职业生涯从指导阶段发展到在资助的指导阶段，我将接受质谱、体外脂质体融合测定、膜生物化学和 tomosyn-2 基因敲除小鼠的生成方面的培训。在指导阶段进行的研究将检查已确定的磷酸化位点对 tomosyn-2 调节胰岛素分泌的能力的影响，并了解 tomosyn-2 靶向蛋白体降解的机制。我的研究将研究 tomosyn-2 通过调节可溶性 N-乙基马来酰亚胺敏感因子附着蛋白受体 (SNARE) 蛋白的活性来抑制胰岛素分泌的机制，并表征新型药物的作用tomosyn-2 结合蛋白。这些研究将为 tomosyn-2 抑制胰岛素分泌的机制提供新的线索，并将进一步加深我们对 T2D 胰岛素分泌调节的理解。