Deciphering the role of miR-33 in central regulation of feeding behavior

项目总结/摘要 这是内森·普莱斯博士的KO 1奖申请书耶鲁大学医学院的副研究员 学校他的研究重点是确定参与细胞生物能量调节的新因子， 确定这些因素如何促进与肥胖、衰老和肥胖相关的疾病的发展， 代谢综合征本研究的主要目的是：（1）确定miR-33的缺失是如何影响miR-33的表达的。 AgRP神经元中的AgRP影响大脑对代谢稳态的调节，（2）建立特异性 miR-33介导这些效应的机制，以及（3）为Price博士提供经验和技能 这是他成为独立研究者和追求未来研究目标的必要条件。先前工作 已经确定miR-33是脂质代谢、线粒体功能和脂肪酸代谢的重要调节因子， 氧化，并证明了抗miR-33治疗剂用于治疗心血管疾病的有效性。 动物模型中的疾病。然而，最近的工作表明，全身miR-33的丢失会导致 由于食物摄入量增加，易患肥胖症和代谢功能障碍。 大脑对摄食行为的调节主要通过AgRP和POMC神经元介导， 分别促进饥饿和饱足的信号。拟议的研究战略将利用新的 开发了在AgRP神经元中缺乏miR-33的小鼠模型，该神经元负责促进进食 行为所提供的初步数据表明，AgRP神经元中miR-33的缺失促进肥胖， 代谢功能的方式类似于全身miR-33缺陷。这项工作将涉及一个深入 分析AgRP神经元中miR-33对摄食和肥胖调节的具体影响，以及 确定miR-33介导这些作用的机制。利用尖端技术， 识别仅在AgRP神经元中活跃翻译的mRNA的变化将使我们能够识别miR-33靶点， 在缺乏miR-33的AgRP神经元中表达增加。此外，我们将能够评估 这些基因可能参与介导miR-33对肥胖和代谢功能的影响， 选择性地敲除AgRP神经元中的特定靶基因。这项工作将提供一个改进的 了解miR-33调节肥胖和代谢功能的机制，并提供 对治疗代谢性疾病可能的新机制的必要洞察。拟议 研究也将促进博士价格的成长作为一个研究人员提供经验，研究中心 调节新陈代谢，促进新技能的发展，可用于他未来的研究。 博士普莱斯的导师和合作者将监督他在这些领域的培训，并提供专业知识和 开展拟议研究所需的经验。他们沿着普莱斯医生的顾问委员会， 帮助指导他的职业发展，使他最终成为一名独立的学术研究者。

PROJECT SUMMARY/ABSTRACT This is an application for a KO1 Award for Nathan Price Ph.D., an associate research scientist at Yale Medical School. His research focuses on identifying novel factors involved in the regulation of cellular bioenergetics and determining how these factors contribute to the development of diseases associated with obesity, aging, and metabolic syndrome. The primary objectives of the proposed research are (1) to determine how loss of miR-33 in AgRP neurons impacts regulation of metabolic homeostasis by the brain, (2) establish the specific mechanisms by which miR-33 mediates these effects, and (3) provide Dr. Price with the experience and skills necessary to establish himself as an independent investigator and pursue his future research goals. Prior work has established miR-33 as an important regulator of lipid metabolism, mitochondrial function, and fatty acid oxidation, and demonstrated the effectiveness of anti-miR-33 therapeutics for the treatment of cardiovascular disease in animal models. However, recent work has demonstrated that whole body loss of miR-33 results in a strong predisposition to the development of obesity and metabolic dysfunction, due to increased food intake. Regulation of feeding behavior by the brain is primarily mediated through AgRP and POMC neurons, which promote signals of hunger and satiety, respectively. The proposed research strategy will utilize a newly developed mouse model that lacks miR-33 in AgRP neurons, which are responsible for promoting feeding behavior. The preliminary data provided indicate that loss of miR-33 in AgRP neurons promotes obesity and metabolic function in a manner similar to whole body miR-33 deficiency. This work will involve an in-depth analysis of the specific impact of miR-33 in AgRP neurons on the regulation of feeding and obesity, and determine the mechanisms by which miR-33 mediates these effects. Utilization of cutting edge techniques for identifying changes in actively translated mRNAs only in AgRP neurons will allow us to identify miR-33 targets that have increased expression in AgRP neurons lacking miR-33. Furthermore, we will be able to assess the likelihood that these genes are involved in mediating the effects of miR-33 on obesity and metabolic function by selectively knocking down specific target genes only in AgRP neurons. This work will provide an improved understanding of the mechanisms by which miR-33 regulates obesity and metabolic function, and offer necessary insight into possible new mechanisms for the treatment of metabolic diseases. The proposed research will also facilitate Dr. Price’s growth as a researcher by providing experience in studying central regulation of metabolism, and promoting the development of new skills that can be utilized in his future research. Dr. Price’s mentors and collaborators will oversee his training in these areas, and provide the expertise and experience necessary to carry out the proposed research. They, along with Dr. Price’s advisory committee, will help guide his career development toward his ultimate goal of becoming an independent academic investigator.