Molecular Mechanisms of SOD1-linked ALS (P01)

SOD1 相关 ALS 的分子机制 (P01)

• 批准号: 7631371
• 负责人: JOAN Selverstone VALENTINE
• 金额: $ 118.55万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-08-11 至 2010-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7631371
• 关键词: Molecular; Mechanisms; SOD1; linked; ALS

Missense mutations in copper-zinc superoxide dismutase (SOD1) are linked to autosomal- dominant, adult-onset, familial amyotrophic lateral sclerosis (FALS). The principal investigators of this application plan a concerted,synergistic approach to determine how these SOD1 mutations relate to ALS. Dr. J.S. Valentine's laboratory has a long track record in the study of SOD1 metallobiochemistry. Dr. P.J. Hart's laboratory has over 10 years experience in 3-D structure and function studies of normal and pathogenic SOD1. Dr. D.R. Borchelt has an established track record in using transgenic mice to study mechanisms of SOD1-linked FALS. Together, we will use a three- pronged approach to dissecting the toxic mechanism(s) of mutant SOD1 - chemistry (Project 1),3- D structure and solution biophysical properties (Project 2), and disease-specific function (Project 3). To support these projects, we will have a Core that provides analytical support in the form of proteomics, mass spectrometry, and ICP-MS metal analysis. Our general approach is to characterize SOD1 proteins encoding novel mutations that target a particular chemical or structural feature of the protein. After thorough in vitro characterization, we will examine, in vivo, the ability of these novel SOD1 proteins to cause motor neuron disease. The Project goals are to: 1) understand the role of oxidative chemistry in both direct and indirect modes of toxicity to motor neurons; 2) understand the consequences of oxidative damage to SOD1 on its structure and its solution properties; 3) determine the structural elements in SOD1 that predispose it to produce non-native homo- (or hetero-) polymeric interactions, and to understand their role in toxicity to motor neurons; and 4) understand the causes and consequences of mutant SOD aggregation by characterizing the SOD1 protein that is found within these aggregates as well as by characterizing other proteins that may be contained within these structures. Through our combined efforts we will be able to define structure and disease-function relationships at an unprecedented level.

铜锌超氧化物歧化酶（SOD 1）的错义突变与常染色体- 显性、成人发病、家族性肌萎缩性侧索硬化症（FALS）。的主要研究人员 本申请计划一种协调的、协同的方法来确定这些SOD 1突变如何 与ALS有关J.S.博士瓦伦丁的实验室在SOD 1的研究方面有着悠久的历史。 金属生物化学P. J.哈特博士的实验室在3D结构方面有超过10年的经验， 正常和致病性SOD 1的功能研究。D.R.博士Borchelt有一个既定的记录 使用转基因小鼠研究SOD 1相关的FALS的机制。我们一起用三个- 深入剖析突变SOD 1-化学毒性机制的方法（项目1），3- D结构和解决方案的生物物理性质（项目2），和疾病特异性功能（项目3）。 为了支持这些项目，我们将有一个核心，以 蛋白质组学、质谱和ICP-MS金属分析。我们的一般做法是 表征编码靶向特定化学或结构的新突变的SOD 1蛋白 蛋白质的特征。在彻底的体外表征之后，我们将在体内检查 这些新的SOD 1蛋白导致运动神经元疾病。本项目的目标是：1）了解 氧化化学在运动神经元直接和间接毒性模式中的作用; 2） 了解SOD 1的氧化损伤对其结构的影响及其解决方案 性质; 3）确定SOD 1中使其产生非天然 同（或异）聚合物相互作用，并了解其在运动神经元毒性中的作用; 和4）理解突变SOD聚集的原因和后果， 在这些聚集体中发现的SOD 1蛋白以及通过表征 可能包含在这些结构中。通过我们的共同努力，我们将能够确定 结构和疾病功能关系达到前所未有的水平。