OXIDATIVE STRESS AND DEGENERATION OF MOTOR NEURONS

描述 多种机制被认为导致运动神经元(MN)在 肌萎缩侧索硬化症(ALS)包括兴奋性毒性和氧化 压力。拟议中的研究验证了氧自由基的假设 线粒体堆积在肌萎缩侧索硬化症的发病机制中起主要作用。 通过促进膜脂过氧化，破坏离子稳态 以及运动神经元的凋亡。许多常染色体显性遗传性家族性遗传病 ALS是由铜/锌-超氧化物歧化酶错义突变引起的。我会雇佣一个类似MN的人 人ALS细胞系及转基因小鼠模型的建立 铜/锌-超氧化物歧化酶基因致MN死亡及临床表现 与人类肌萎缩侧索硬化症类似，阐明与肌萎缩侧索硬化相关的MN死亡机制。 我认为线粒体MnSOD的过度表达对MNS具有保护作用 抗细胞凋亡，通过抑制线粒体氧自由基的产生和 膜脂过氧化。拟议中的研究将阐明 MN退变的机制与MN退变有关 ALS的发病机制，并将确定潜在的预防和 人类肌萎缩侧索硬化症的治疗方法。

DESCRIPTION Multiple mechanisms has been postulated to cause motor neuron (MN) in amyotrophic lateral sclerosis (ALS) including excitotoxicity and oxidative stress. The proposed studies test the hypothesis that oxyradical accumulation in mitochondria plays a major role in the pathogenesis of ALS by promoting membrane lipid peroxidation, disruption of ion homeostasis and apoptosis in motor neurons. Many cases of autosomal dominant familial ALS result from missense mutation in Cu/Zn-SOD. I will employ a MN-like cell line and transgenic mouse model of ALS in which expression of human CU/Zn-SOD gene result in MN death generation and a clinical profile similar to human ALS, to elucidate mechanisms of MN death relevant to ALS. I propose that over-expression of mitochondrial MnSOD can protect MNs against apoptosis, by suppressing mitochondrial oxyradical production and membrane lipid peroxidation. The proposed research will elucidate mechanisms of MN degeneration of MN degeneration relevant to the pathogenesis of ALS, and will identify potential preventative and therapeutic approaches for human ALS patients.