Gpr17 function in metabolism and satiety control

描述(申请人提供)：该研究所的长期研究计划是研究治疗糖尿病和肥胖症的中枢神经系统途径。这一独立之路奖的主要目标是提供必要的培训和研究经验，以促进PI向独立研究职业的过渡。有了这个奖项，PI将能够扩大她在新陈代谢研究方面的知识，获得各种新技术的专业知识，并为未来的研究和研究资金申请生成数据。肥胖症的流行以惊人的速度增长。肥胖患者通常会患上心血管疾病、糖尿病和肾脏疾病等并存疾病。需要发现新的可用药途径来对抗肥胖症。中枢神经系统(CNS)中的下丘脑感知并整合激素和营养线索，从而对能量平衡发挥协调调节作用。作为可操作的治疗靶点的下丘脑通路的知识仍然有限。PI和她的导师最近在AgRP神经元中发现了一条新的通路，作为肥胖治疗的潜在靶点。叉头盒蛋白O1(FoxO1)影响胰岛素和瘦素信号通路。在AgRP神经元中带有FoxO1基因敲除的小鼠减少了食物摄入量，减少了瘦身，并改善了血糖控制。PI对FoxO1缺乏的AgRP神经元进行了分类，并将G蛋白偶联受体Gpr17确定为FoxO1的靶标。这项研究直接考察了Gpr17信号在AgRP神经元中的生理功能和分子机制。本项目的目的是：1)确定Gpr17在能量平衡和糖代谢中的作用；2)阐明Gpr17信号在AgRP神经元中的分子机制。研究方法将包括建立转基因小鼠模型、代谢表型、细胞信号分析和神经生理学分析。国际和平研究所聚集了一支优秀的顾问和合作者团队，他们拥有综合的专业知识，就拟议研究的各个方面以及她的职业生涯向她提供建议。此外，哥伦比亚大学糖尿病研究中心为博士后的职业生涯提供良好的培训环境和坚实的支持 发展。PI认为，拟议的项目非常适合启动她在代谢研究领域的独立研究生涯。

DESCRIPTION (provided by applicant): 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.