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：
8538967
负责人：
Congcong He
金额：
$ 9万
依托单位：
UT SOUTHWESTERN MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-09-01 至 2013-09-04
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8538967
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 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

DESCRIPTION (provided by applicant): 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.

描述（由申请人提供）：本 K99/R00 独立之路奖申请的目的是研究新型自噬基因 beclin 2 在预防 2 型糖尿病和肥胖症中的功能和机制。2 型糖尿病是一种代谢性疾病。其特点是胰腺功能不全 ¿然而，肥胖相关的 2 型糖尿病的发病机制目前尚不完全清楚，自噬的激活和大麻素受体 1 (CB1R) 信号的下调都与预防肥胖相关。在博士后培训期间，我发现并克隆了一种属于 Beclin（卷曲螺旋、肌球蛋白样 BCL2 相互作用蛋白）的新型哺乳动物特异性自噬基因。家庭、beclin 2 和我的初步数据表明，beclin 的破坏 2 对自噬、CB1R 运输和周转以及代谢调节具有显着影响。在本应用中，我将重点研究 Beclin 2 在体外和体内自噬和 CB1R 运输/信号转导中的机制：目标 1 描述了分子机制（ s) Beclin 2在自噬调节中的作用，通过生化方法和结构功能研究Beclin 2的蛋白质-蛋白质相互作用，研究Beclin 2的功能和机制；其中 Beclin 2 调节 CB1R 降解和信号转导，并研究 Beclin 2 的这种功能与其在自噬中的作用是否相关；Aim 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，以响应常规饮食和高饮食。脂肪饮食挑战，使用我最近生成的敲除小鼠模型（beclin 2-/-）和条件敲除小鼠模型（beclin 2flox/flox）。阐明自噬在代谢调节中的作用和细胞机制，并帮助了解自噬的治疗操作对代谢疾病的影响，在德克萨斯大学西南医学中心的支持下，我将得到国际公认的领导者的指导。自噬和新陈代谢领域，这将有助于我的研究生涯向独立研究者职位的转变。