Genetic Analysis of Fas in Motor Neuron Cell Death

描述（由申请人提供）：该提案概述了Fas受体信号传导导致运动神经元自然发生和病理性细胞死亡这一假设的遗传学检验。亨德森实验室先前的研究已经确定了生长因子停药后运动神经元死亡的自分泌信号机制，该机制需要Fas配体的诱导和Fas受体的激活。随后的表征这一过程揭示了运动神经元特异性信号传导途径的Fas受体，需要nNOS和高度致敏的转基因小鼠模型中的突变体SOD 1过表达的ALS。我们的具体目标是：（1）描述FasL在运动神经元发育过程中的作用，（2）用相关报告基因产生Fas的条件无效，（3）在ALS小鼠模型中遗传学检测Fas信号对突变型SOD 1相关运动神经元细胞死亡的贡献。使用一组既定的标准分析运动功能，动物行为和组织组织学，我们将检查正常的发育细胞死亡和病理性细胞死亡的进展，在SOD突变小鼠的Fas破坏的后果，并将定义在这两个过程中Fas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.