A novel autophagy gene beclin 2 in the prevention of type 2 diabetes and obesity

新型自噬基因 beclin 2 预防 2 型糖尿病和肥胖

基本信息

批准号：
8774357
负责人：
Congcong He
金额：
$ 24.9万
依托单位：
NORTHWESTERN UNIVERSITY AT CHICAGO
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：
2014-01-01 至 2016-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8774357
关键词：
Adverse effects Agonist Alleles Animal Model Animals Autophagocytosis Award BCL2 gene Back Behavior Binding Biochemical Blindness Blood Candidate Disease Gene Cardiovascular Diseases Cell surface Cells Cholesterol Complex Data Degradation Pathway Development Diabetes Mellitus Diet Disease Down-Regulation Eating Embryo Employee Strikes Exercise Fatty acid glycerol esters Fibroblasts G Protein-Coupled Receptor Signaling G-Protein-Coupled Receptors Gene Mutation Genes Genetic Global Change Human Human Cell Line Immunoprecipitation In Vitro Incidence Insulin Resistance Kidney Failure Knock-in Mouse Knock-out Knockout Mice Knowledge Leptin Life Style Ligands Light Link Location Lysosomes Mass Spectrum Analysis Measures Mediating Medical center Mentors Metabolic Metabolic Diseases Metabolism Methods Molecular Mus Myosin ATPase Neonatal Non-Insulin-Dependent Diabetes Mellitus Nutrient Obesity Organ Organelles Pancreas Pathogenesis Pathway interactions Phosphotransferases Play Population Positioning Attribute Prevention Protein Family Proteins Recycling Regulation Research Research Personnel Rodent Role Signal Transduction Small Interfering RNA Sorting - Cell Movement Starvation Stress Stroke Structure Testing Texas Therapeutic Tissues Triglycerides Universities abstracting adiponectin cannabinoid receptor career clinical application diabetes mellitus therapy diabetic genetic linkage high risk in vitro activity in vivo insulin sensitivity mouse model mutant neuropsychiatry novel post-doctoral training prevent protein protein interaction research study response trafficking trait

项目摘要

Project Summary/Abstract The objective of this K99/R00 Pathway to Independence Award application is to study the functions and mechanisms of a novel autophagy gene beclin 2 in the prevention of type 2 diabetes and obesity. Type 2 diabetes is a metabolic disorder characterized by the inability of pancreatic ¿ cells to compensate for body insulin resistance, often accompanied by obesity. However, the pathogenesis of obesity-related type 2 diabetes is incompletely understood. Recently, both activation of autophagy and downregulation of the cannabinoid receptor 1 (CB1R) signaling have been implicated in preventing diabetes/obesity. During my postdoctoral training, I discovered and cloned a novel mammalian-specific autophagy gene belonging to the Beclin (coiled-coil, myosin-like BCL2-interacting protein) family, beclin 2, and my preliminary data showed that the disruption of beclin 2 has striking effects on autophagy, CB1R trafficking and turnover, and metabolic regulation. In this application, I will focus on studying the mechanisms of Beclin 2 in autophagy and CB1R trafficking/signaling in vitro and in vivo: Aim 1 characterizes the molecular mechanism(s) of Beclin 2 in the regulation of autophagy, through biochemical methods and structure-function studies of protein-protein interactions of Beclin 2; Aim 2 investigates the function and mechanisms by which Beclin 2 regulates CB1R degradation and signaling, and study whether this function of Beclin 2 interrelates with its role in autophagy; and Aim 3 studies the in vivo functions of Beclin 2 in maintaining insulin sensitivity and preventing obesity in response to regular diet and high-fat diet challenge, using a knockout mouse model (beclin 2-/-) and a conditional knockout mouse model (beclin 2flox/flox) that I have recently generated. These studies will shed light on the role and cellular mechanisms of autophagy in metabolic regulation, and help understand the impact of therapeutic manipulation of autophagy in metabolic diseases. Under the auspices of the University of Texas Southwestern Medical Center, I will be mentored by internationally recognized leaders in the fields of autophagy and metabolism, which will aid the transition of my research career toward an independent investigator position.

项目摘要/摘要该K99/R00独立奖项申请的目的是研究功能和新型自噬基因beclin 2在预防2型糖尿病和肥胖症中的机制。类型2 糖尿病是一种代谢性疾病，其特征是胰腺无法补偿身体胰岛素抵抗，通常伴有肥胖。但是，肥胖相关类型2的发病机理糖尿病尚不完全理解。最近，自噬的激活和下调大麻素受体1（CB1R）信号已在预防糖尿病/肥胖症中暗示。在我期间博士后训练，我发现并克隆了一个属于该基因的新型哺乳动物特异性自噬基因 Beclin（卷曲螺旋，类肌球蛋白样Bcl2相互作用蛋白），beclin 2，我的初步数据表明 Beclin 2的破坏对自噬，CB1R贩运和转弯以及代谢有惊人的影响规定。在此应用中，我将重点研究自噬和CB1R中Beclin 2的机制体外和体内的运输/信号传导：AIM 1表征了Beclin 2的分子机制通过生化方法和蛋白质蛋白质的结构功能研究对自噬进行调节 Beclin 2的相互作用； AIM 2研究了Beclin 2调节CB1R的功能和机制降解和信号传导，并研究Beclin 2的这种功能是否与其在自噬中的作用相关； AIM 3研究Beclin 2在维持胰岛素敏感性和防止肥胖症中的体内功能使用淘汰小鼠模型（Beclin 2 - / - ）和A 我最近生成的条件敲除小鼠模型（Beclin 2flox/flox）。这些研究将浮出水面关于自噬在代谢调节中的作用和细胞机制，并有助于了解代谢疾病中自噬的治疗操纵。在德克萨斯大学的主持下西南医学中心，国际认可的领导人将考虑我自噬和新陈代谢，这将有助于我的研究职业过渡到独立研究者职位。