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.

Public Health Relevance

Project Obesity-associated type 2 diabetes is a multifactorial metabolic disease, and imposes high risks for cardiovascular disease, stroke, blindness and renal failure. Recently, autophagy has been implicated in preventing the pathogenesis of type 2 diabetes. This proposed study is to elucidate the functions and mechanisms of a novel autophagy gene beclin 2, to establish new connections between autophagy, degradation of G protein-coupled receptors and metabolic regulation, and to provide knowledge on the identification of novel disease targets and development of more efficient therapies for diabetes, obesity and relevant metabolic disorders.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Career Transition Award (K99)
Project #
5K99DK094980-02
Application #
8538967
Study Section
Diabetes, Endocrinology and Metabolic Diseases B Subcommittee (DDK)
Program Officer
Haft, Carol R
Project Start
2012-09-01
Project End
2013-09-04
Budget Start
2013-09-01
Budget End
2013-09-04
Support Year
2
Fiscal Year
2013
Total Cost
$90,000
Indirect Cost
$6,667
Name
University of Texas Sw Medical Center Dallas
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
800771545
City
Dallas
State
TX
Country
United States
Zip Code
75390
He, Congcong; Wei, Yongjie; Sun, Kai et al. (2013) Beclin 2 functions in autophagy, degradation of G protein-coupled receptors, and metabolism. Cell 154:1085-99