Role of Fas death receptor signaling in motor neuron degeneration

描述（由申请人提供）：项目摘要-肌萎缩侧索硬化症（ALS）患者的有效治疗方法的开发目前受到缺乏有效治疗靶点的阻碍。我们的长期目标是使用基于运动神经元的细胞和动物模型来更好地了解ALS中涉及的分子和细胞机制，并验证这些作为临床干预的靶点。从家族性ALS模型SOD 1突变小鼠纯化的运动神经元显示出对涉及Fas死亡受体和一氧化氮的新细胞死亡途径（称为Fas/NO途径）的活化的选择性加剧的敏感性。在症状前SOD 1小鼠的脊髓中，该通路的所有元件都被激活。该项目将解决四个问题：（a）Fas/NO途径是否是SOD 1突变小鼠体内疾病过程的重要贡献者？(b)哪些细胞类型参与体内Fas/NO通路的激活？(c)突变的SOD 1如何使运动神经元对Fas/NO通路的激活敏感？(d)Fas/NO通路与人类散发性ALS的相关性是什么？我们将Fas和FasL的条件性敲除小鼠与SOD 1突变小鼠交叉，并测量对运动功能、存活率和病理学的影响。我们将使用生物标志物方法分析Fas在体内的作用位点。最后，我们将分析Fas/NO通路的元素在散发性ALS患者脊髓切片上的表达。总的来说，这项工作将提供新的见解运动神经元变性的机制在体外和体内，并应允许验证新的治疗目标在家族性和散发性ALS。肌萎缩性侧索硬化症（ALS），更好地称为Lou Gehrig病，迅速导致患者瘫痪和死亡，反映了运动神经元的进行性丧失，脊髓中控制肌肉运动的神经细胞。这项研究将使用细胞和动物模型，以更好地了解ALS的分子事件，作为制定合理治疗策略的手段。

DESCRIPTION (provided by applicant): Project Summary- Development of effective treatments for patients with amyotrophic lateral sclerosis (ALS) is currently hindered by the lack of validated therapeutic targets. Our long-term goal is to use motor neuron-based cell and animal models to better understand the molecular and cellular mechanisms involved in ALS, and to validate these as targets for clinical intervention. Motor neurons purified from SOD1 mutant mice, a model of familial ALS, show selectively exacerbated sensitivity to activation of a new cell death pathway involving the Fas death receptor and nitric oxide (referred to as the Fas/NO pathway). All elements of the pathway are activated in the spinal cord of presymptomatic SOD1 mice. The project will address four questions: (a) Is the Fas/NO pathway an essential contributor to the disease process in vivo in SOD1 mutant mice? (b) Which cell types are involved in activation of the Fas/NO pathway in vivo? (c) How does mutant SOD1 sensitize motor neurons to activation of the Fas/NO pathway? (d) What is the relevance of the Fas/NO pathway to sporadic ALS in humans? We will cross conditional knockout mice for Fas and FasL to SOD1 mutant mice and measure effects on motor function, survival and pathology. We will analyze the sites of Fas action in vivo using a biomarker approach. Lastly, we will analyze expression of elements of the Fas/NO pathway on sections of spinal cord from human patients with sporadic ALS. Overall, the work will provide new insights into mechanisms of motor neuron degeneration in vitro and in vivo and should allow for validation of new therapeutic targets in both familial and sporadic ALS. Relevance Amyotrophic lateral sclerosis (ALS), better known as Lou Gehrig's disease, leads rapidly to paralysis and death of patients, reflecting progressive loss of motor neurons, the nerve cells in the spinal cord that control muscle movement. This study will use cell and animal models to better understand the molecular events that underlie ALS as a means for developing rational therapeutic strategies.