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

描述（由申请人提供）：本K99/R 00 Pathway to Independence Award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，其特征是胰腺细胞无法补偿身体胰岛素抵抗，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（CB 1 R）信号转导的下调都与预防糖尿病/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属于Beclin（卷曲螺旋，肌球蛋白样BCL 2相互作用蛋白）家族的拟南芥特异性自噬基因，beclin 2，我的初步数据显示， 2在自噬、CB 1 R运输和周转以及代谢调节方面具有显著的作用。在本申请中，我将重点研究Beclin 2在体内外自噬和CB 1 R运输/信号转导中的机制：目的1通过生物化学方法和Beclin 2蛋白质-蛋白质相互作用的结构-功能研究来表征Beclin 2在自噬调控中的分子机制;目的2研究Beclin 2调控CB 1 R降解和信号转导的功能和机制，并探讨Beclin 2的这种功能是否与其在自噬中的作用相关; Aim 3研究了Beclin 2在维持胰岛素敏感性和预防肥胖中的体内功能，以响应常规饮食和高脂饮食的挑战，使用我最近产生的敲除小鼠模型（beclin 2-/-）和条件敲除小鼠模型（beclin 2flox/flox）。这些研究将揭示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在代谢疾病中的作用。在德克萨斯大学西南医学中心的主持下，我将接受自噬和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者的转变。

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.