mTOR Signaling in Striatum: Regulation and Function

纹状体中的 mTOR 信号传导：调节和功能

• 批准号: 9174387
• 负责人: Srinivasa Subramaniam
• 金额: $ 2.35万
• 依托单位: SCRIPPS FLORIDA
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-01-01 至 2020-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9174387
• 关键词: Address; Affect; Amino Acids; Animal Model; Behavior; Binding; Biochemical; Biochemistry; Biology; Brain; Brain region; Burn injury; Cell Culture Techniques; Cell physiology; Cells; Corpus striatum structure; Cultured Cells; Data; Development; Diabetes Mellitus; Disease; Embryonic Development; Epilepsy; FRAP1 gene; Figs - dietary; Functional disorder; Genetic; Goals; Growth; Guanosine Triphosphate Phosphohydrolases; Homologous Gene; Human; Huntington Disease; Intervention; Knowledge; L-DOPA induced dyskinesia; Link; Malignant Neoplasms; Mediating; Mental Retardation; Mission; Modification; Molecular; Motor; Mus; Nervous System Physiology; Neurons; Neurotransmitters; Outcome; Pain; Parkinson Disease; Pathogenesis; Pathology; Pathway interactions; Pharmacology; Phenotype; Phosphotransferases; Play; Population; Prevention approach; Preventive; Protein-Serine-Threonine Kinases; Public Health; Publishing; Regulation; Research; Role; Signal Transduction; Small Interfering RNA; Testing; Therapeutic; Therapeutic Intervention; Toxic effect; Work; anxiety-like behavior; associated symptom; base; brain dysfunction; cell behavior; cognitive function; disability; field study; in vitro Assay; in vitro activity; in vivo; innovation; insight; intercellular communication; interdisciplinary approach; motor control; mouse model; nervous system disorder; new therapeutic target; novel; novel therapeutics; public health relevance; ras Guanine Nucleotide Exchange Factors; targeted treatment; ubiquitin-protein ligase

 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.

 描述（由申请人提供）：mTOR是一种多功能激酶，参与胚胎发育、癌症和糖尿病。然而，它在神经系统生理学和疾病中的作用和调节仍然不太清楚。这是一个主要问题，因为mTOR活性的功能障碍（高或低）与影响脑中特定神经元群体的各种脑功能障碍有关，例如癫痫、智力迟钝、亨廷顿病（HD）和帕金森病（PD）。详细了解mTOR是如何调节的，以及它在选择性大脑区域中发挥什么作用，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激活mTOR的纹状体富集的Rhes（纹状体中富集的Ras同源物）GTdR（Subramaniam，2012）如何在纹状体中被操纵以用于预防和治疗目的。这里的目标，这是追求我们目标的下一步，是研究Rhes GTdR在培养细胞中调节mTOR的机制，并测试纹状体中mTOR缺失对体内运动行为的影响。我们的中心假设是Rhes GT3是纹状体中mTOR的主要调节因子，并且Rhes-mTOR回路控制纹状体功能和功能障碍。我们的假设是基于我们发表的数据制定的，表明Rhes GTdR除了作为SUMO E3连接酶和HD中纹状体细胞毒性的调节剂外，还激活mTOR信号传导，其介导PD中的异常运动行为。我们建议进一步确认调节机制，以及如何，Rhes激活纹状体中的mTOR。我们将具体解决以下问题：目的1：解剖纹状体mTORC 1激活的RasGRP 1-Rhes电路的机制;目的2：确定SUMO化在Rhes介导的mTORC 1活性中的作用;目的3：测试mTOR纹状体缺失对小鼠行为和纹状体病理学的影响。总的来说，我们的提议在概念上是创新的，因为它结合了多学科方法-细胞培养，动物模型，生物化学，药理学，细胞信号传导和行为-以发现纹状体特异性作用和调节Rhes-mTOR信号传导。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传导的基础生物学的理解，并有助于开发与Rhes-mTOR功能障碍相关的神经系统疾病（如HD和PD）的新疗法和治疗方法。