mTOR Signaling in Striatum: Regulation and Function

 描述(申请人提供)：mTOR是一种多功能的激酶，与胚胎发育、癌症和糖尿病有关。然而，它在神经系统生理学和疾病中的作用和调节仍然知之甚少。这是一个大问题，因为mTOR活动的故障(无论是高还是低)都与各种大脑功能障碍有关，这些功能障碍会影响大脑中特定的一组神经元，如癫痫、智力低下、亨廷顿病(HD)和帕金森病(PD)。详细了解mTOR是如何调节的，以及它在选择性脑区域中扮演什么角色，对于制定更好的干预策略非常重要。我们的长期目标是了解我们发现的激活mTOR(Subramaniam，2012)的纹状体富含RHES(纹状体中Ras同源富集型)GTPase是如何在纹状体中被操纵以达到预防和治疗的目的。我们的下一步目标是研究Resh GTP酶调节培养细胞mTOR的机制，并测试纹状体mTOR缺失对体内运动行为的影响。我们的中心假设是，Rkets GTPase是纹状体mTOR的主要调节因子，Rkets-mTOR回路控制纹状体功能和功能障碍。我们的假说是在我们已发表的数据的基础上提出的，表明Resh GTPase除了作为相扑E3连接酶和HD的纹状体细胞毒性调节因子外，还激活了mTOR信号，从而介导了PD的异常运动行为。我们建议进一步确认RHES激活纹状体内mTOR的机制。我们将具体解决以下问题：目的1：剖析RASGRP1-RHES通路在纹状体mTORC1激活中的作用机制；目的2：确定SUMO化在RHES介导的mTORC1活性中的作用；以及目标3：测试纹状体mTOR缺失对小鼠行为和纹状体病理的影响。总体而言，我们的建议在概念上是创新的，因为它结合了多学科的方法-细胞培养、动物模型、生物化学、药理学、细胞信号和行为-以发现纹状体特有的Resh-mTOR信号的作用和调节。该项目的结果将是重要的，因为它将促进我们对纹状体信号的基本生物学基础的理解，并有助于开发治疗神经系统疾病的新疗法和治疗方法，如与Resh-mTor功能障碍相关的HD和PD。

 DESCRIPTION (provided by applicant): mTOR is a multifunctional kinase involved in embryonic development, cancer, and diabetes. Its role and regulation in nervous system physiology and disease, however, remains less understood. This is a major problem, because the malfunction of mTOR activity (either high or low) has been linked to a variety of brain dysfunctions that affect a specific set of neuronal populations in the brain, such as epilepsy, mental retardation, Huntington's disease (HD), and Parkinson's disease (PD). A detailed understanding of how mTOR is regulated and what role it plays in selective brain regions is important for the development of better intervention strategies. Our long-term goal is to understand how striatum-enriched Rhes (Ras homolog-enriched in striatum) GTPase, which we found to activate mTOR (Subramaniam, 2012), can be manipulated in the striatum for preventive and therapeutic purposes. The objective here, which is the next step in pursuit of our goal, is to investigate the mechanisms by which Rhes GTPase regulates mTOR in cultured cells, and test the effect of mTOR deletion in the striatum on motor behaviors in vivo. Our central hypothesis is that Rhes GTPase is a major regulator of mTOR in the striatum, and that Rhes-mTOR circuitry controls striatal functions and dysfunctions. Our hypothesis has been formulated on the basis of our published data, demonstrating that Rhes GTPase, besides its role as a SUMO E3 ligase and regulator of striatal cell toxicity in HD, activates mTOR signaling, which mediates abnormal motor behaviors in PD. We propose to further confirm the mechanisms what regulates, and how, Rhes activates mTOR in the striatum. We will specifically address the following: Aim 1: Dissect the mechanisms of RasGRP1-Rhes circuitry in striatal mTORC1 activation; Aim 2: Identify the role of SUMOylation in Rhes-mediated mTORC1 activity; and Aim 3: Test the effect of striatal deletion of mTOR on mouse behavior and striatal pathology. Overall, our proposal is conceptually innovative as it combines multidisciplinary approaches- cell culture, animal models, biochemistry, pharmacology, cell signaling and behavior- to discover the striatal-specific role and regulation of Rhes-mTOR signaling. The results of this project will be significant, as it will advance our understanding of not on the fundamentals biology of striatal signaling and also help develop novel therapies and treatments for neurological disorders, such as HD and PD, which are associated with Rhes-mTOR dysfunctions.