Genetic Analysis of Fas in Motor Neuron Cell Death

描述(由申请人提供)：这项提案概述了对Fas受体信号有助于运动神经元自然发生和病理性细胞死亡这一假设的基因测试。亨德森实验室以前的研究已经确定了生长因子停用后运动神经元死亡的自分泌信号机制，这需要Fas配体的诱导和Fas受体的激活。随后对这一过程的表征揭示了Fas受体的运动神经元特异性信号通路，该通路需要nNOS，并且在突变SOD1过度表达的ALS转基因小鼠模型中高度敏感。我们的具体目标是(1)确定FasL在运动神经元发育中的作用，(2)用连锁报告产生Fas的条件空，以及(3)在ALS小鼠模型中从遗传学角度检验Fas信号在突变的SOD1连锁运动神经元死亡中的作用。利用一系列已建立的分析运动功能、动物行为和组织组织学的标准，我们将研究Fas干扰对正常发育细胞死亡和SOD突变小鼠病理性细胞死亡的影响，并将确定Fas在这两个过程中的表达。

DESCRIPTION (provided by applicant): This proposal outlines a genetic test of the hypothesis that signaling by the Fas receptor contributes to naturally occurring and pathologic cell death of motor neurons. Previous research from the Henderson laboratory has identified an autocrine signaling mechanism for motor neuron death following growth factor withdrawal that requires the induction of Fas ligand and activation of the Fas receptor. Subsequent characterization of this process revealed a motor neuron specific signaling pathway for the Fas receptor that requires nNOS and is highly sensitized in transgenic mouse models of ALS in which mutant SOD1 is overexpressed. Our specific aims are to (1) Characterize the role of FasL during motor neuron development, (2) Generate a conditional null for Fas with a linked reporter, and (3) Genetically test the contribution of Fas signaling to mutant SOD1 linked motor neuron cell death in a mouse model of ALS. Using a battery of established criteria for analyzing motor function, animal behavior, and tissue histology, we will examine the consequences of Fas disruption on normal developmental cell death and the progression of pathologic cell death in the SOD mutant mice, and will define the expression of Fas during both processes.