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：
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
项目类别：
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

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（应用程序提供）：MTOR是一种参与胚胎发育，癌症和糖尿病的多功能激酶。然而，它在神经系统生理和疾病中的作用和调节仍然不太容易理解。这是一个主要问题，因为MTOR活性（高或低）的故障已与影响大脑中一组特定神经元群体的多种脑功能障碍有关，例如癫痫，智力低下，亨廷顿氏病（HD）和帕金森氏病（PD）。对MTOR的调节方式及其在选择性大脑区域中扮演什么角色的详细理解对于发展更好的干预策略至关重要。我们的长期目标是了解如何在预防性和治疗的纹状体中操纵富含纹状体的Rhes（RAS同源物中的RAS同源物）GTPase（Subramaniam，2012）。目的。这里的目标是追求我们目标的下一步，是研究Rhes GTPase调节培养细胞中MTOR的机制，并测试MTOR缺失在纹状体中对体内运动行为的影响。我们的中心假设是Rhes GTPase是纹状体中MTOR的主要调节剂，并且Rhes-Mtor电路控制纹状体功能和功能障碍。我们的假设是基于我们已发布的数据提出的，表明Rhes GTPase除了其作为HD中的SUMO E3连接酶和纹状体细胞毒性的调节剂外，还激活了MTOR信号，它介导PD中的异常运动行为。我们将具体解决以下内容：目标1：剖析纹状体MTORC1激活中RASGRP1粘附电路的机理；目标2：确定sumoylation在Rhes介导的MTORC1活性中的作用；和目标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 - 发现纹状体特异性的作用和瑞斯 - 麦托信号的调节。该项目的结果将是重要的，因为它将提高我们对纹状体信号传导的基本生物学的理解，还有助于开发与HD和PD等神经系统疾病的新型疗法和治疗，这些疗法与Rhes-MTOR功能障碍有关。