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

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.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Transition Award (R00)
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Special Emphasis Panel (NSS)
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Haft, Carol R
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Northwestern University at Chicago
Anatomy/Cell Biology
Schools of Medicine
United States
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Fernández, Álvaro F; Sebti, Salwa; Wei, Yongjie et al. (2018) Disruption of the beclin 1-BCL2 autophagy regulatory complex promotes longevity in mice. Nature 558:136-140
Yamamoto, Soh; Kuramoto, Kenta; Wang, Nan et al. (2018) Autophagy Differentially Regulates Insulin Production and Insulin Sensitivity. Cell Rep 23:3286-3299
Rocchi, Altea; He, Congcong (2017) Activating Autophagy by Aerobic Exercise in Mice. J Vis Exp :
Rocchi, Altea; He, Congcong (2017) Regulation of Exercise-Induced Autophagy in Skeletal Muscle. Curr Pathobiol Rep 5:177-186
Shi, Bo; Huang, Qi-Quan; Birkett, Robert et al. (2017) SNAPIN is critical for lysosomal acidification and autophagosome maturation in macrophages. Autophagy 13:285-301
Park, Jong Kook; Peng, Han; Katsnelson, Julia et al. (2016) MicroRNAs-103/107 coordinately regulate macropinocytosis and autophagy. J Cell Biol 215:667-685
Klionsky, Daniel J (see original citation for additional authors) (2016) Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition). Autophagy 12:1-222
Kuramoto, Kenta; Wang, Nan; Fan, Yuying et al. (2016) Autophagy activation by novel inducers prevents BECN2-mediated drug tolerance to cannabinoids. Autophagy 12:1460-71
Rocchi, Altea; He, Congcong (2015) Emerging roles of autophagy in metabolism and metabolic disorders. Front Biol (Beijing) 10:154-164
Zhang, Weiran; He, Congcong (2014) Regulation of plasma membrane receptors by a new autophagy-related BECN/Beclin family member. Autophagy 10:1472-3