Nuclear Hormone Receptor Regulation in C elegans

描述(由申请人提供) 核激素受体(NHR)由一类转录因子组成 参与许多生物过程，包括饮食新陈代谢。因此， 事实证明，NHR是治疗肥胖症和 糖尿病。NHR在活体中发挥作用的机制相当 然而，情况复杂，许多治疗方法因药物而变得无效 耐药性和不良副作用。通过我的工作，我希望提升我们的 了解国家人权机构如何在发展和发展的各个方面发挥作用 动态平衡。这一理解有望导致产生 更好的基于NHR的糖尿病、肥胖症和其他人类疾病的治疗。 我的长期战略是开发一个系统来描述NHR的监管 活体网络。为了实现我的目标，我选择使用 线虫作为研究国家人权的模式生物。线虫 为在体内研究转录因子提供了几个优点，并为 将分子功能与不同的生理过程联系起来。我会观察的 并量化活体动物的NHR活动，并评估 对NHR活动的监管因素。此外，我将使用这个系统来 发现NHR功能和生理过程之间的联系。 在这笔赠款所涵盖的时间内，我将重点学习几项技能 这将对设置我上面描述的系统很有用。首先，我会 学习计算机编程方法和染色质免疫沉淀技术 并采用它们来识别NHR的靶基因。第二，我将获得专业知识 在蠕虫生理学和解剖学方面，并利用这一专业知识来构建GFP记者 有了它，我可以可视化和量化体内的NHR调节。最后，我会 学习开发用于鉴定的化学提取方法 作为线虫NHR调节因子的小分子配体。这个 成功完成这项提案中概述的目标将大大 推动启动一个独立的研究实验室，该实验室有能力 立竿见影地生产。

DESCRIPTION (provided by applicant) Nuclear hormone receptors (NHRs) comprise a class of transcription factors that are involved in many biological processes, including dietary metabolism. Thus NHRs have proven to be attractive drug targets for the treatment of obesity and diabetes. The mechanisms by which NHRs function in living organisms are quite complex however, and many therapeutic approaches become ineffective due to drug resistance and undesirable side-effects. Through my work, I hope to enhance our understanding of how NHRs function in all aspects of development and homeostasis. This understanding would hopefully lead to the production of better NHR based therapies for diabetes, obesity, and other human maladies. My long-term strategy is to develop a system for characterizing NHR regulatory networks in vivo. In order to accomplish my goals I have chosen to use the roundworm C. elegans as a model organism for investigating NHRs. C. elegans provides several advantages for studying transcription factors in vivo, and for linking molecular functions to distinct physiological processes. I will observe and quantify NHR activity in live animals, and assess the contribution of regulatory factors to NHR activity. Additionally, I will use this system to discover the links between NHR function and physiological processes. In the period covered by this grant I will focus on adopting several skills that will be useful for setting up the system I described above. First, I will learn computer programming methods and chromatin immunoprecipitation techniques and adopt them to identify NHR target genes. Second, I will acquire expertise in worm physiology and anatomy and use this expertise to build GFP reporters with which I can visualize and quantify NHR regulation in vivo. Finally, I will learn to develop chemical extraction methods for the identification of small-molecule ligands that serve as regulators of C. elegans NHRs. The successful completion of the goals outlined in this proposal will greatly facilitate the initiation of an independent research lab that has the capacity to be immediately productive.