Gpr17 function in metabolism and satiety control

描述（申请人提供）：主要研究者的长期研究计划是研究基于中枢神经系统的糖尿病和肥胖症治疗途径。这个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的过渡到一个独立的研究生涯。有了这个奖项，PI将能够扩大她在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的应用生成数据。肥胖症的流行率以惊人的速度增长。肥胖患者通常会出现合并症，如心血管疾病、糖尿病和肾病。需要发现新的药物途径来对抗肥胖。中枢神经系统（CNS）的下丘脑感知并整合激素和营养线索，从而对能量稳态施加协调调节。下丘脑通路作为可操作的治疗靶点的知识仍然有限。PI和她的导师最近确定了AgRP神经元中的一种新途径，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。AgRP神经元FoxO 1敲除的小鼠食物摄入量减少、消瘦，血糖控制改善。PI分析流式分选FoxO1缺陷的AgRP神经元，并鉴定G蛋白偶联受体Gpr17为FoxO1靶标。该研究直接研究了AgRP神经元中Gpr17信号转导的生理功能和分子机制。本研究的目的是：1）确定Gpr17在能量平衡和葡萄糖代谢中的作用; 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测定。PI已经召集了一个由顾问和合作者组成的优秀团队，他们拥有综合专业知识，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研究员提供了良好的培训环境和坚实的职业支持 发展PI认为，拟议的项目非常适合在代谢研究领域开展她的独立研究生涯。

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.