mTOR activation and function during CNTF signaling

CNTF 信号传导过程中 mTOR 的激活和功能

• 批准号: 7174223
• 负责人: STEVEN A REEVES
• 金额: $ 31.17万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-07-24 至 2008-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7174223
• 关键词: Adult; Alzheimer' s Disease; Amyotrophic Lateral Sclerosis; Brain; Cell physiology; Central Nervous System Diseases; Cerebellar Ataxia; Ciliary Neurotrophic Factor; Clinical; Clinical Trials; Complex; Development; Disease; Event; Foundations; Gene Expression; Huntington Disease; Laboratories; Link; Maps; Memory; Nerve Degeneration; Nervous system structure; Neurons; Pathway interactions; Play; Prevention; Proteins; Reporting; Research; Role; STAT3 gene; Signal Pathway; Signal Transduction; Signal Transduction Pathway; Sirolimus; Stroke; Synaptic plasticity; Testing; Therapeutic Agents; Work; analog; base; cytokine; injured; neuronal survival; novel; receptor; research study; sound; transcription factor

DESCRIPTION (provided by applicant): Signal transduction initiated by the neuroregulatory cytokine ciliary neurotrophic factor (CNTF) has been shown to promote neuronal survival in the injured or diseased nervous system. These findings have provided a basis for using CNTF as a therapeutic agent aimed at the treatment or prevention of a variety of neuropathological diseases, including amyotrophic lateral sclerosis, Huntington's disease, Alzheimer's disease, stroke, and several forms of cerebellar ataxias. The precise manner in which CNTF activates and coordinately regulates the signaling cascades it employs for its neuroprotective effects remains largely undefined. One important component in this cascade that we have recently identified is the mammalian target of rapamycin (mTOR). The TOR proteins have been shown to be key regulators of a diverse set of cell processes, and recent reports have indicated that mTOR may play a critical role in synaptic plasticity and memory. We hypothesize that mTOR is a critical link in one or more of the CNTF signal transduction pathways. Thus the research we are proposing in this application aims to determine the mechanism by which CNTF activates mTOR and to identify the role(s) that mTOR plays in CNTF-stimulated sympathetic neurons. This work could identify novel targets for therapies aimed at the treatment or prevention of a variety of central nervous system disorders as well as provide a sound scientific foundation for the clinical use of CNTF and CNTF analogues now being tested in clinical trials.

描述（由申请人提供）：由神经调节细胞因子睫状神经营养因子（CNTF）引发的信号转导已被证明可以促进受损或患病神经系统中的神经元存活。这些发现为使用CNTF作为旨在治疗或预防多种神经病理性疾病的治疗剂提供了基础，包括肌萎缩侧索硬化症、亨廷顿病、阿尔茨海默病、中风和几种形式的小脑性共济失调。 CNTF 激活和协调调节其用于神经保护作用的信号级联的精确方式在很大程度上仍不清楚。我们最近发现的这一级联中的一个重要组成部分是雷帕霉素的哺乳动物靶点（mTOR）。 TOR 蛋白已被证明是多种细胞过程的关键调节因子，最近的报告表明 mTOR 可能在突触可塑性和记忆中发挥关键作用。我们假设 mTOR 是一个或多个 CNTF 信号转导途径的关键环节。因此，我们在本申请中提出的研究旨在确定 CNTF 激活 mTOR 的机制，并确定 mTOR 在 CNTF 刺激的交感神经元中发挥的作用。这项工作可以确定旨在治疗或预防各种中枢神经系统疾病的新疗法靶点，并为目前正在临床试验中测试的 CNTF 和 CNTF 类似物的临床使用提供坚实的科学基础。

项目成果

Simvastatin induces cell death in a mouse cerebellar slice culture (CSC) model of developmental myelination.

辛伐他汀在小鼠小脑切片培养 (CSC) 发育髓鞘形成模型中诱导细胞死亡。

• DOI: 10.1016/j.expneurol.2008.09.010
• 发表时间: 2009
• 期刊: Experimental neurology
• 影响因子: 5.3
• 作者: Xiang,Zhongmin;Reeves,StevenA
• 通讯作者: Reeves,StevenA

Peroxisome-proliferator-activated receptor gamma coactivator 1 α contributes to dysmyelination in experimental models of Huntington's disease.

过氧化物酶体增殖物激活受体 γ 共激活剂 1α 有助于亨廷顿病实验模型中的髓鞘形成障碍。

• DOI: 10.1523/jneurosci.1291-11.2011
• 发表时间: 2011
• 期刊: The Journal of neuroscience : the official journal of the Society for Neuroscience
• 作者: Xiang,Zhongmin;Valenza,Marta;Cui,Libin;Leoni,Valerio;Jeong,Hyun-Kyung;Brilli,Elisa;Zhang,Jiangyang;Peng,Qi;Duan,Wenzhen;Reeves,StevenA;Cattaneo,Elena;Krainc,Dimitri
• 通讯作者: Krainc,Dimitri