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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：
8989093
负责人：
Congcong He
金额：
$ 23.6万
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/8989093
关键词：
Adverse effects Agonist Alleles Animal Model Animals Autophagocytosis Award Back Behavior Binding Biochemical Blindness Blood CB1 knockout CNR1 gene Candidate Disease Gene Cardiovascular Diseases Cell surface Cells Cholesterol Complex DNA Sequence Alteration 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 Genes Genetic Global Change HRK gene High Fat Diet 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 career clinical application diabetes mellitus therapy diabetic genetic linkage high risk in vitro activity in vivo insulin sensitivity knock-down 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.

项目概要/摘要 K99/R00 独立之路奖申请的目的是研究其功能和新型自噬基因 beclin 2 预防 2 型糖尿病和肥胖的机制。 2型糖尿病是一种代谢性疾病，其特征是胰腺细胞无法代偿身体胰岛素抵抗，常伴有肥胖。然而，与肥胖相关的 2 型肥胖的发病机制糖尿病尚不完全了解。最近，自噬的激活和自噬的下调大麻素受体 1 (CB1R) 信号传导与预防糖尿病/肥胖有关。在我的在博士后培训期间，我发现并克隆了一种新的哺乳动物特异性自噬基因，该基因属于 Beclin（卷曲螺旋，肌球蛋白样 BCL2 相互作用蛋白）家族，beclin 2，我的初步数据表明 beclin 2 的破坏对自噬、CB1R 运输和周转以及代谢具有显着影响规定。在本次申请中，我将重点研究Beclin 2在自噬和CB1R中的机制体外和体内转运/信号传导：目标 1 描述了 Beclin 2 在体内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调节自噬 Beclin 2 的相互作用；目标 2 研究 Beclin 2 调节 CB1R 的功能和机制降解和信号转导，并研究 Beclin 2 的这种功能是否与其在自噬中的作用相关；目标 3 研究 Beclin 2 在维持胰岛素敏感性和预防肥胖方面的体内功能使用敲除小鼠模型 (beclin 2-/-) 和我最近生成的条件敲除小鼠模型（beclin 2flox/flox）。这些研究将揭示研究自噬在代谢调节中的作用和细胞机制，并有助于理解自噬的影响代谢疾病中自噬的治疗操作。在德克萨斯大学的赞助下西南医学中心，我将得到以下领域国际公认的领导者的指导自噬和新陈代谢，这将有助于我的研究生涯向独立的转变调查员职位。