Protein Expression, Nitration and Gene Changes in ALS

描述（由申请人提供）： 过量NO的致病作用在几种神经退行性疾病中是明显的。 疾病，包括肌萎缩性侧索硬化症（ALS）。虽然假设 已经被提出来解释ALS中的运动神经元死亡， 仍然没有答案。一种发病机制模型具有过量的NO，或其 代谢产物，与细胞衍生的活性氧反应，导致 蛋白质硝化，这通常与组织损伤有关， 条件然而，关于蛋白质的分子后果知之甚少。 过量NO和蛋白质硝化。我们假设过量的NO和相关的 蛋白质硝化引起改变表达的重要变化， 细胞中关键蛋白的功能。我们提出了一个蛋白质组学和基因阵列研究 全面评估基因或蛋白质表达的变化， 硝化，在两种不同的ALS小鼠模型和人类脊髓中 组织.我们将：1）确定蛋白质的表达和/或硝化变化 2）确定已确定的硝化残留物中的硝化残留物 蛋白质;和3）鉴定在疾病期间表达水平改变的基因 进展通过这些方法揭示的候选蛋白质和基因将产生 我们认为，至少在以下三个领域会有增长：新基因 以及ALS研究的蛋白质靶点。初步结果表明， 可能会受到影响，包括那些参与细胞周期， 代谢、细胞运动、细胞结构和伤口修复。会有一个 迫切需要研究其表达或硝化作用的变化如何影响 在ALS中起作用。这项工作应导致新的目标， 治疗干预神经退行性变的潜在机制-基因和 蛋白质的变化是独特的和共同的每一种疾病模型-将是 鉴定常见的变化可能揭示了 神经退行性变，从而影响了对亨廷顿病的基础研究， 帕金森氏症，阿尔茨海默氏症，和SMA疾病。诊断和治疗候选人 基因和蛋白质，应该提供有用的新的诊断标记。这些 包括疾病进展、治疗功效和 高通量药物发现。我们对非神经元组织的研究可能会发现 提供更方便监测的标记。

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.