Superoxide Dismutase, Peroxynitrite and ALS
超氧化物歧化酶、过氧亚硝酸盐和 ALS
基本信息
- 批准号:8073045
- 负责人:
- 金额:$ 31.34万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2008
- 资助国家:美国
- 起止时间:2008-06-01 至 2013-05-31
- 项目状态:已结题
- 来源:
- 关键词:AccountingActive SitesAddressAffectAgreementAmericanAmyotrophic Lateral SclerosisAnimalsAntioxidantsAutopsyBindingBinding SitesBrainCopperCu-Superoxide DismutaseCuprozinc Superoxide DismutaseDataDevelopmentDiseaseDisulfidesDorsalEnvironmental HealthEnzymesFamilial Amyotrophic Lateral SclerosisFourier transform ion cyclotron resonanceFree RadicalsHealthHeartHornsHumanIn VitroLeadLigand BindingLinkMapsMass Spectrum AnalysisMeasurableMeasuresMetalsMethodsMolecularMolecular ChaperonesMotor Neuron DiseaseMotor NeuronsMusMutationNitric OxideOxidation-ReductionParalysedPatientsPeroxonitritePredispositionProcessProteinsRattusRoleSiteSonSpatial DistributionSpinalSpinal CordStagingSuperoxide DismutaseSuperoxidesTestingToxic effectTransgenic AnimalsTransgenic MiceTransgenic OrganismsTyrosineZincZinc deficiencybasecopper zinc superoxide dismutasedimerdisulfide bondgain of functionin vivoinnovationkillingsmutantnitrationoverexpressionprotein aggregationresearch studytheoriestool
项目摘要
DESCRIPTION (provided by applicant): Description ALS is a fatal progressive paralysis affecting 34,000 Americans and killing 8,000 per year. The discovery in 1993 of dominant mutations to Cu,Zn-superoxide dismutase (Cu,Zn-SOD) linked to 2-7% of ALS cases led to hopes that new treatments for ALS based on antioxidants might be forthcoming. Whereas there is broad agreement that ALS mutant SODs have impaired stability, the specific toxic gain-of-function associated with these mutations is still hotly debated. The two leading explanations are the aggregation hypothesis that aggregation of mutant SODs is a direct cause of disease and the zinc-deficient hypothesis that disease is due to increased redox activity of SOD that has lost zinc but retains copper in its active site. We propose, based on extensive preliminary evidence, that the two hypotheses are intimately interconnected with aggregation being paradoxically protective by removing zinc-deficient SOD. The zinc-deficient hypothesis also raises the intriguing possibility that SOD could contribute to sporadic ALS. We have developed innovative mass spectrometric methods to quantitively the metal content of SOD across the spinal cord, which allow us to critically evaluate the zinc-deficient and aggregation hypotheses. Aim 1 will characterize how the dimer interface and the intramolecular disulfide of SOD are affected by ALS-associated mutations to affect zinc and copper binding as well as propensity for aggregation of SOD. This aim will explore the physical basis underlying metal loss and aggregation to understand how mutant SODs are more prone to losing zinc and why mutant SODs are dominant in inheritance. Aim 2 will assess how the concentrations of zinc-deficient SOD are modulated by CCS (the copper chaperone for SOD) and wild-type Cu,Zn SOD in transgenic animals both of which accelerate disease in vivo -- and how to most effectively pharmacologically decrease zinc-deficient SOD in vivo. Aim 3 will map the anatomical distribution of the different metal states of SOD in disease-affected versus unaffected regions in human sporadic ALS patients, testing whether zinc-deficient SOD may be the common connection between sporadic and familial SOD. New preliminary data demonstrate a vast improvement in sensitivity with the FTICR that makes Aim 3 feasible. Completion of the proposed experiments will critically test how SOD mutations lead to the development of ALS and whether loss of zinc occurs from wild-type SOD in sporadic ALS. PUBLIC HEALTH RELEVANCE: Only a small percentage of patients with Lou Gehrig's disease (also known as ALS) carry mutations to a common antioxidant defense enzyme called SOD. Completion of the proposed experiments will help explain how SOD can be involved in the vast majority of sporadic ALS patients who do not have SOD mutations, which will point to new ways to treat the disease. We specifically are testing the hypothesis that this enzyme becomes toxic when it loses one zinc atom and have developed new mass spectrometric methods that directly measure the loss of zinc directly from the spinal cord.
ALS是一种致命的进行性瘫痪,影响34,000名美国人,每年造成8,000人死亡。1993年发现的与2-7%的ALS病例相关的Cu,Zn-SOD的显性突变导致了基于抗氧化剂的ALS新治疗方法的希望。虽然有广泛的共识,ALS突变SOD的稳定性受损,与这些突变相关的特定毒性功能获得仍然是激烈的争论。两个主要的解释是聚集假说,即突变SOD的聚集是疾病的直接原因,以及缺锌假说,即疾病是由于SOD的氧化还原活性增加,失去了锌,但保留在其活性部位的铜。我们建议,广泛的初步证据的基础上,这两个假设是密切相关的聚集是矛盾的保护,通过去除缺锌SOD。缺锌假说也提出了一个有趣的可能性,即SOD可能有助于散发性ALS。我们已经开发出创新的质谱方法,以定量的金属含量的SOD在整个脊髓,这使我们能够严格评估锌缺乏和聚集的假设。目的1将表征二聚体界面和SOD的分子内二硫化物如何受到ALS相关突变的影响,从而影响锌和铜结合以及SOD聚集的倾向。这一目标将探索金属损失和聚集的物理基础,以了解突变SOD如何更容易失去锌,以及为什么突变SOD在遗传中占主导地位。目的2将评估CCS(SOD的铜伴侣)和野生型Cu,Zn SOD在转基因动物中如何调节缺锌SOD的浓度,这两种酶都加速体内疾病-以及如何最有效地抑制体内缺锌SOD。目的3将映射不同金属状态的SOD在人类散发性ALS患者的疾病影响与未受影响的区域的解剖分布,测试是否锌缺乏SOD可能是散发性和家族性SOD之间的共同联系。新的初步数据表明,FTICR的灵敏度大大提高,使目标3可行。完成拟议的实验将严格测试SOD突变如何导致ALS的发展,以及在散发性ALS中野生型SOD是否会发生锌的丢失。公共卫生相关性:只有一小部分患有Lou Gehrig病(也称为ALS)的患者携带一种称为SOD的常见抗氧化防御酶的突变。完成拟议的实验将有助于解释SOD如何参与绝大多数没有SOD突变的散发性ALS患者,这将为治疗该疾病指明新的方法。我们特别测试了这种酶在失去一个锌原子时变得有毒的假设,并开发了新的质谱方法,直接测量脊髓中锌的损失。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
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JOSEPH S BECKMAN其他文献
JOSEPH S BECKMAN的其他文献
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{{ truncateString('JOSEPH S BECKMAN', 18)}}的其他基金
Reducing Susceptibility to Environmental Stress Throughout the Life Span
降低整个生命周期对环境压力的敏感性
- 批准号:
7901764 - 财政年份:2009
- 资助金额:
$ 31.34万 - 项目类别:
Superoxide Dismutase, Peroxynitrite and ALS
超氧化物歧化酶、过氧亚硝酸盐和 ALS
- 批准号:
8269706 - 财政年份:2008
- 资助金额:
$ 31.34万 - 项目类别:
Superoxide Dismutase, Peroxynitrite and ALS
超氧化物歧化酶、过氧亚硝酸盐和 ALS
- 批准号:
7624971 - 财政年份:2008
- 资助金额:
$ 31.34万 - 项目类别:
Superoxide Dismutase, Peroxynitrite and ALS
超氧化物歧化酶、过氧亚硝酸盐和 ALS
- 批准号:
7527886 - 财政年份:2008
- 资助金额:
$ 31.34万 - 项目类别:
Superoxide Dismutase, Peroxynitrite and ALS
超氧化物歧化酶、过氧亚硝酸盐和 ALS
- 批准号:
7848812 - 财政年份:2008
- 资助金额:
$ 31.34万 - 项目类别:
Functional Significance of Tyrosine Nitration in Proteins
蛋白质中酪氨酸硝化的功能意义
- 批准号:
7559166 - 财政年份:2007
- 资助金额:
$ 31.34万 - 项目类别:
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