Protein Expression, Nitration and Gene Changes in ALS

描述(由申请人提供)： 过量的NO在几种神经退行性变中的致病作用是明显的 疾病，包括肌萎缩侧索硬化症(ALS)。尽管假设 已经提出用来解释肌萎缩侧索硬化症运动神经元死亡的基本问题 仍未得到答复。一种发病机制的模型是NO过量，或者它的 代谢物，与细胞衍生的活性氧物种反应，导致 蛋白质硝化，这通常与组织损伤有关 条件。然而，人们对这种病毒的分子后果知之甚少。 过量的NO和蛋白质硝化。我们假设过量的NO和相关的 蛋白质硝化引起重要的变化，改变表达和 关键蛋白在细胞中的功能。我们建议进行蛋白质组学和基因阵列研究。 对基因或蛋白质表达和蛋白质的变化进行全局评估 在两种不同的ALS小鼠模型和人脊髓中的硝化作用 组织。我们将：1)确定其表达和/或硝化改变的蛋白质 与病情进展；2)鉴定鉴定中的硝化残留物(S) 蛋白质；以及3)确定在疾病过程中表达水平变化的基因 进步。通过这些方法揭示的候选蛋白质和基因将创建 眼前的利益，我们预计至少有三个领域的增长：新基因 和研究肌萎缩侧索硬化症的蛋白质靶标。初步结果显示范围很广 可能受到影响的蛋白质，包括那些参与细胞周期的蛋白质， 新陈代谢、细胞运动、细胞结构和伤口修复。将会有一个 迫切需要检查它们的表达或硝化作用的变化如何影响 在肌萎缩侧索硬化症的背景下发挥作用。这项工作应该会带来新的目标 治疗性干预。神经退行性变的潜在机制--基因和 在每个疾病模型中既独特又常见的蛋白质变化-将是 已确认身份。共同的变化可能揭示出 神经退化，从而影响对亨廷顿氏症的基础研究， 帕金森氏症、阿尔茨海默氏症和SMA病。诊断和治疗-候选 基因和蛋白质应该会提供有用的新诊断标记。这些 包括疾病进展、治疗效果和 高通量药物发现。我们对非神经元组织的研究可能会发现 提供更方便的监控的标记。

DESCRIPTION (provided by applicant): A pathogenic role for excess NO is apparent in several neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS). Although hypotheses have been proposed to explain motor neuron death in ALS, fundamental questions remain unanswered. One model for pathogenesis has excess NO, or its metabolites, reacting with cell-derived reactive oxygen species, resulting in protein nitration, which is often associated with tissue damage in this condition. However, little is known regarding the molecular consequences of excess NO and protein nitration. We hypothesize that excess NO and associated protein nitration cause important changes that alter the expression and function of key proteins in cells. We propose a proteomic and gene array study to globally evaluate changes in gene or protein expression, and protein nitration, in two different mouse models for ALS and in human spinal cord tissue. We will: 1) Identify proteins whose expression and/or nitration changes with disease progression; 2) Identify the nitrated residue(s) in the identified proteins; and 3) Identify genes whose expression levels change during disease progression. Candidate proteins and genes revealed by these methods will create immediate interest, and we envision growth in at least three areas: New gene and protein targets for ALS research. Preliminary results suggest a wide range of proteins may be affected, including those involved in cell-cycling, metabolism, cell-motility, cell-structure, and wound repair. There will be an immediate need to examine how changes in their expression or nitration affect function within the context of ALS. This work should lead to new targets for therapeutic intervention. Underlying mechanisms of neurodegeneration - gene and protein changes that are both unique and common to each disease model - will be identified. Common changes may reveal fundamental mechanisms for neurodegeneration, and thus impact basic research into Huntington's, Parkinson's, Alzheimer's, and SMA disease. Diagnosis and therapy-candidate genes, and proteins, should provide useful new diagnostic markers. These include markers for disease progression, treatment efficacy, and high-throughput drug discovery. Our work with non-neuronal tissue may identify markers that provide far more-convenient monitoring.