mTOR Signaling in Striatum: Regulation and Function

纹状体中的 mTOR 信号传导：调节和功能

基本信息

批准号：
9282509
负责人：
Srinivasa Subramaniam
金额：
$ 42万
依托单位：
SCRIPPS FLORIDA
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-06-01 至 2020-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9282509
关键词：
Address Affect Amino Acids Animal Model Behavior Binding Biochemical Biochemistry Biology Brain Brain region Cell Culture Techniques Cell physiology Cells Corpus striatum structure Cultured Cells Data Development Diabetes Mellitus Disease Disease model Embryonic Development Epilepsy FRAP1 gene Functional disorder Genetic Goals Growth Factor 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 Phosphorylation Phosphotransferases Physiological 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 United States National Institutes of Health Work associated symptom base brain dysfunction cell behavior cognitive function disability field study in vitro Assay in vitro activity in vivo innovation insight interdisciplinary approach motor control mouse model nervous system disorder new therapeutic target novel novel therapeutics public health relevance ubiquitin-protein ligase

项目摘要

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 是一种参与胚胎发育、癌症和糖尿病的多功能激酶，然而，由于 mTOR 的功能障碍，其在神经系统生理学和疾病中的作用和调节仍知之甚少。活动（高或低）与多种脑功能障碍有关，这些功能障碍会影响大脑中特定的一组神经元群，例如癫痫、智力低下、亨廷顿病 (HD) 和帕金森病详细了解 mTOR 的调节方式及其在选择性大脑区域中的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纹状体中富含 Ras 同源物的机制。我们发现 GTP 酶可以激活 mTOR（Subramaniam，2012），可以在纹状体中进行操作，以达到预防和治疗的目的。为了实现我们的目标，我们的下一步是研究Rhes GTPase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 GTPase是mTOR的主要调节剂。 mTOR 位于纹状体中，Rhes-mTOR 电路控制纹状体功能和功能障碍。我们的假设是根据我们发表的数据制定的，证明了 Rhes GTPase 除了其作为 SUMO 的作用外。 HD 中的 E3 连接酶和纹状体细胞毒性调节剂激活 mTOR 信号传导，从而介导 PD 中的异常运动行为。我们建议进一步确认 Rhes 激活纹状体中 mTOR 的机制和方式。目标 1：剖析 RasGRP1-Rhes 电路在纹状体 mTORC1 激活中的机制；目标 2：确定 SUMO 化在 Rhes 介导中的作用； mTORC1 活性；目标 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。发现 Rhes-mTOR 信号传导的纹状体特异性作用和调节该项目的结果将是意义重大的，因为它将增进我们对纹状体信号传导基础生物学的理解，并有助于开发新的疗法。以及与 Rhes-mTOR 功能障碍相关的神经系统疾病（例如 HD 和 PD）的治疗。