Gpr17 function in metabolism and satiety control

Gpr17 在新陈代谢和饱腹感控制中的功能

• 批准号: 9294050
• 负责人: Hongxia Ren
• 金额: $ 24.34万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-07-01 至 2019-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9294050
• 关键词: Ablation; Address; Adipose tissue; Affect; Agonist; Anatomy; Animal Model; Appetite Regulation; Award; Biological Assay; Body Weight; Cardiovascular Diseases; Collaborations; Comorbidity; Coupled; Cues; Data; Desire for food; Diabetes Mellitus; Eating; Energy Metabolism; Environment; Fasting; Functional disorder; Funding; Future; G-Protein-Coupled Receptors; GTP-Binding Protein alpha Subunits, Gs; Genetic; Goals; High Fat Diet; Homeostasis; Hormonal; Hypothalamic structure; Indirect Calorimetry; Injection of therapeutic agent; Insulin; Intervention; Islets of Langerhans; Kidney Diseases; Knock-out; Knockout Mice; Knowledge; Label; Laboratories; Learning; Leptin; Light; Measures; Mentors; Metabolic; Metabolism; Molecular; Motor Activity; Mus; Nature; Neuraxis; Neurons; Nutrient; Nutritional; Obesity; Oxygen Consumption; Pathway interactions; Patients; Peptides; Peripheral; Pharmacologic Substance; Phase; Physiological; Play; Postdoctoral Fellow; Prevalence; Property; Proteins; Public Health; RNA Interference; Regulation; Reporter; Reporter Genes; Research; Research Methodology; Research Personnel; Respiration; Role; Satiation; Signal Pathway; Signal Transduction; Solid; Stomach; Techniques; Testing; Thinness; Training; Transgenic Mice; Translating; Universities; base; blood glucose regulation; career; career development; combat; energy balance; experience; flexibility; glucose metabolism; glycemic control; improved; in vivo; insulin secretion; insulin sensitivity; knock-down; loss of function; mTOR Signaling Pathway; metabolic phenotype; mouse model; neurophysiology; neuroregulation; novel; novel therapeutics; public health relevance; reduced food intake; response; sensor; targeted treatment; therapeutic target; transcription factor

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.

描述（由申请人提供）： PI 的长期研究计划是研究基于中枢神经系统的途径来治疗糖尿病和肥胖症。该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。凭借该奖项，PI 将能够扩展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经费申请生成数据。肥胖症的患病率正以惊人的速度增长。肥胖患者经常出现合并症，例如心血管疾病、糖尿病和肾脏疾病。需要发现新的药物途径来对抗肥胖。中枢神经系统（CNS）中的下丘脑感知并整合激素和营养信号，从而对能量稳态进行协调调节。关于下丘脑通路作为可行治疗靶点的知识仍然有限。 PI 和她的导师最近发现了 AgRP 神经元中的一条新途径，可以作为肥胖治疗的潜在目标。叉头盒蛋白 O1 (FoxO1) 影响胰岛素和瘦素信号通路。 AgRP 神经元中 FoxO1 敲除的小鼠的食物摄入量减少，体重减轻，血糖控制得到改善。 PI 对缺乏 FoxO1 的 AgRP 神经元进行流式分选分析，并确定 G 蛋白偶联受体 Gpr17 作为 FoxO1 的靶标。该研究直接研究了 AgRP 神经元中 Gpr17 信号传导的生理功能和分子机制。该项目的目的是：1）确定Gpr17在能量平衡和葡萄糖代谢中的作用； 2）阐明AgRP神经元中Gpr17信号传导的分子机制。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 聚集了一支由顾问和合作者组成的优秀团队，他们具有综合专业知识，可以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了良好的培养环境和坚实的支持 发展。 PI 认为所提议的项目非常适合开启她在代谢研究领域的独立研究生涯。