The PI's long-term research plan is to study the central nervous system-based pathways for the treatment of diabetes and obesity. The primary goal of this Pathway to Independence Award is to provide necessary training and research experience to facilitate the PI's transition to an independent research career. With this award, the PI will be able to expand her knowledge in metabolic research, acquire expertise in a variety of novel techniques, and generate data for future studies and applications for research funding. The prevalence of obesity has grown at an alarming rate. Obese patients often develop comorbidities, such as cardiovascular disease, diabetes, and renal disorders. Novel druggable pathways need to be discovered to combat obesity. The hypothalamus in the central nervous system (CNS) senses and integrates hormonal and nutritional cues, and thereby exerts coordinated regulation on energy homeostasis. Knowledge of hypothalamic pathways as actionable therapeutic targets remains limited. The PI and her mentor have recently identified a novel pathway in AgRP neurons as a potential target for obesity therapy. Forkhead box protein O1 (FoxO1) impinges on both insulin and leptin signaling pathways. Mice with FoxO1 knockout in AgRP neurons have reduced food intake, leanness, and improved glycemic control. The PI profiled flow- sorted FoxO1-deficient AgRP neurons and identified G protein-coupled receptor, Gpr17, as a FoxO1 target. The proposed research directly examines the physiological function and molecular mechanism of Gpr17 signaling in AgRP neurons.
The aims of this project are to: 1) establish the role of Gpr17 in energy balance and glucose metabolism; 2) elucidate the molecular mechanisms of Gpr17 signaling in AgRP neurons. The research methodology will include establishing transgenic mouse models, metabolic phenotyping, cell signaling analysis, and neurophysiology assays. The PI has gathered an outstanding team of advisors and collaborators with the combined expertise to advise her on all aspects of the proposed study as well as on her career. In addition, the Diabetes Research Center at Columbia University provides excellent training environment and solid support to post-doctoral fellows for their career development. The PI believes that the proposed project is well suited to launch her independent research career in the field of metabolic research.
Obesity and its comorbidities, including diabetes, are serious challenges to public health. Effective and safe targets for obesity therapy have remained elusive. Identifying novel pathways that regulate satiety and metabolic homeostasis will not only advance our knowledge of pathophysiology of obesity and diabetes but also provide potential new pharmaceutical targets for therapeutic purposes. My proposal explores a novel anti-obesity pathway with unusually promising druggability.
| Ren, Hongxia; Lu, Taylor Y; McGraw, Timothy E et al. (2015) Anorexia and impaired glucose metabolism in mice with hypothalamic ablation of Glut4 neurons. Diabetes 64:405-17 |
| Ren, Hongxia; Cook, Joshua R; Kon, Ning et al. (2015) Gpr17 in AgRP Neurons Regulates Feeding and Sensitivity to Insulin and Leptin. Diabetes 64:3670-9 |
