MECHANISMS OF MOTOR NEURON DISEASE

肌萎缩侧索硬化症（ALS）是最可怕的疾病之一， 了解医学。 虽然越来越丧失能力 （监禁）通过渐进性瘫痪，受影响的个人仍然完全 意识到疾病的影响。超氧化物歧化酶突变 1（SOD1）已在家族性ALS病例亚组中确定 （FALS）. 我们的教师，谁有长期的承诺，研究 ALS和动物模型，计划一个高度互动的系列 旨在阐明疾病机制的研究， 具有SOD1突变的转基因（Tg）小鼠。 在我们证明了 一些突变SOD 1在体外损害酶活性，我们认为， 突变蛋白质获得了破坏运动神经的不利性质 神经元 当这些突变体蛋白在Tg小鼠中表达时，突变体 SOD1产生一种类SARS疾病。 在这些小鼠中，我们建议： 研究病理学的特征/演变（具体目标1）; 评估突变蛋白对轴突运输的影响（特异性目的 2）;阐明线粒体损伤、氧化/硝化 损伤和细胞死亡病理学（具体目标3）; 研究兴奋性毒性对运动神经元的作用 退化（具体目标4）;使用策略来确定 特定基因产物对疾病的影响（特定目标5）;以及 确定，在轴突切断范例，是否运动神经元在突变小鼠， 更容易受伤， 在Tg小鼠中沉淀疾病（具体目标6）。 信息从 这些调查将是非常宝贵的分析机制， 疾病的ALS和设计未来的治疗干预措施， 人类

Amyotropic lateral sclerosis (ALS) is among the most terrible illnesses known to medicine. While becoming increasingly incapacitated (imprisoned) by progressive paralysis, affected individuals remain fully aware of the impact of their disease. Mutations in superoxide dismutase 1 (SOD1) have been identified in a subset of cases of familial ALS (FALS). Our faculty, who have long-standing commitments to studies of ALS and animals models, plan a highly interactive series of investigations designed to clarify the mechanisms of disease in transgenic (Tg) mice with SOD1 mutations. After we demonstrated that some mutant SOD1 compromised enzyme activity in vitro, we suggested that the mutant protein acquires an adverse property that destroys motor neurons. When these mutant proteins are expressed in Tg mice, mutant SOD1 produce a FALS-like disorder. In these mice, we propose: to investigate the charter/evolution of pathology (Specific Aim 1); to assess the effects of mutant protein on axonal transport (Specific Aim 2); to clarify the roles of mitochondrial injury, oxidation/nitration damage, and cell death pathology in these processes (Specific Aim 3); to examine the contribution of excitotoxicity to motor neuron degeneration (Specific Aim 4); to use strategies to determine the effects of specific gene products on disease (Specific Aim 5); and to determine, in axotomy paradigms, whether motor neurons in mutant mice are more vulnerable to injury and whether axonal transection precipitates disease in Tg mice (Specific Aim 6). Information from these investigations will be invaluable to analysis the mechanisms of disease in ALS and for designing future therapeutic interventions in humans.