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

描述(申请人提供)：K99/R00独立途径奖申请的目的是研究新的自噬基因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紊乱，其特征是胰腺细胞不能补偿身体的胰岛素抵抗，通常伴有肥胖。然而，肥胖相关的2型糖尿病的发病机制还不完全清楚。最近，自噬的激活和大麻素受体1(CB1R)信号的下调都被认为与预防糖尿病/肥胖有关。在我的博士后培训期间，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，我的初步数据表明，Beclin基因的中断 2对自噬、CB1R转运和周转以及代谢调节有显著影响。在这一应用中，我将重点研究Beclin 2在体内外自噬和CB1R转运/信号传递中的机制：目的1通过对Beclin 2蛋白-蛋白质相互作用的生化方法和结构-功能的研究，表征Beclin 2调控自噬的分子机制(S)；目的2研究Beclin 2调控CB1R降解和信号传递的功能和机制，并研究Beclin 2的这一功能是否与其在自噬中的作用有关；目的3利用我最近建立的基因敲除小鼠模型(Beclin 2-/-)和条件性基因敲除小鼠模型(Beclin 2 Flox/Flox)，研究Beclin 2在维持胰岛素敏感性和预防肥胖方面的体内作用。这些研究将有助于阐明自噬在代谢调节中的作用和细胞机制，并有助于理解自噬治疗操作在代谢性疾病中的影响。在德克萨斯大学西南医学中心的赞助下，我将得到自噬和新陈代谢领域国际公认的领导者的指导，这将有助于我的研究生涯向独立研究员职位的过渡。

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.