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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（由申请人提供）：2型糖尿病（T2D）在西方社会已达到流行病的程度。当胰腺的ß-细胞不能分泌足够的胰岛素来适当调节外周血血糖水平时，就会发生T2D，通常是在肥胖的情况下