mTOR activation and function during CNTF signaling

描述（由申请人提供）：神经调节细胞因子睫状神经营养因子（CNTF）启动的信号转导已被证明可促进损伤或病变神经系统中的神经元存活。这些发现为使用CNTF作为治疗或预防多种神经病理疾病（包括肌萎缩侧索硬化症、亨廷顿氏病、阿尔茨海默病、中风和几种形式的小脑共济失调）的治疗剂提供了基础。CNTF激活和协调调节其神经保护作用的信号级联反应的确切方式在很大程度上仍不清楚。我们最近发现的这个级联中的一个重要组成部分是雷帕霉素（mTOR）的哺乳动物靶点。TOR蛋白已被证明是多种细胞过程的关键调节因子，最近的报道表明mTOR可能在突触可塑性和记忆中起关键作用。我们假设mTOR是一个或多个CNTF信号转导通路的关键环节。因此，我们在本应用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所起的作用。这项工作可以为治疗或预防各种中枢神经系统疾病的治疗方法确定新的靶点，并为临床试验中正在测试的CNTF和CNTF类似物的临床应用提供良好的科学基础。

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.