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

项目摘要/摘要 本K99/R00通向独立奖的途径申请的目标是研究功能和 一种新的自噬基因beclin 2预防2型糖尿病和肥胖的机制。类型2 糖尿病是一种代谢紊乱，其特征是胰腺细胞不能代偿身体。 胰岛素抵抗，常伴有肥胖。然而，肥胖相关的2型糖尿病的发病机制 人们对糖尿病的了解还不完全。最近，自噬的激活和细胞外信号的下调 大麻素受体1(CB1R)信号与预防糖尿病/肥胖症有关。在我的 在博士后培训期间，我发现并克隆了一个新的哺乳动物特有的自噬基因，属于 Beclin(卷曲卷曲，肌球蛋白样BCL2相互作用蛋白)家族，Beclin 2，我的初步数据显示 BECLIN-2的干扰对自噬、CB1R的运输和周转以及代谢有显著影响 监管。在这一应用中，我将重点研究Beclin 2在自噬和CB1R中的机制 体外和体内转运/信号转导：目的1研究Beclin 2在体内的分子机制(S) 通过蛋白质-蛋白质的生化方法和结构-功能研究调节自噬 Beclin 2的相互作用；Aim 2研究Beclin 2调节CB1R的功能和机制 并研究Beclin 2的这一功能是否与其在自噬中的作用相关； 目的3研究Beclin-2在维持胰岛素敏感性和预防肥胖中的体内作用 对常规饮食和高脂肪饮食挑战的反应，使用基因敲除小鼠模型(Beclin 2-/-)和 我最近生成的条件性基因敲除小鼠模型(beclin 2flx/flx)。这些研究将揭示 关于自噬在代谢调节中的作用和细胞机制，并有助于理解 代谢性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，我将在以下领域得到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 调查员位置。

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.