SOD1/Bc1-2 Complex: A Role in Regulating Motor Neuron Cell Death
SOD1/Bc1-2 复合物:调节运动神经元细胞死亡的作用
基本信息
- 批准号:7569968
- 负责人:
- 金额:$ 41.75万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2006
- 资助国家:美国
- 起止时间:2006-08-02 至 2011-01-31
- 项目状态:已结题
- 来源:
- 关键词:AffectAffinityAmyotrophic Lateral SclerosisAntibodiesAntioxidantsApoptosisApoptoticAppearanceB-LymphocytesBH3 DomainBindingBiological AssayBrain StemCell Culture TechniquesCell DeathCell FractionationCell SurvivalCellsCerebellumCessation of lifeCo-ImmunoprecipitationsComplexConfocal MicroscopyCorrelation StudiesCyclosporineCytochromesDataDoctor of PhilosophyDown-RegulationDrosophila genusEpitopesExhibitsFlow CytometryGoalsHippocampus (Brain)HumanImmunofluorescence ImmunologicImmunoprecipitationIn VitroInjection of therapeutic agentKnockout MiceLinkLiverLongevityMediatingMitochondriaModelingModificationMolecularMolecular WeightMotor CortexMotor NeuronsMusNatureNerve DegenerationNeuroblastomaNeuronsOxidative StressPathogenesisPatientsPeptidesPhysiologicalProductionPropertyProteinsRattusRegulationReportingResearch PersonnelResistanceRoleSeriesSpecificitySpinalSpinal CordStaurosporineStructureSwellingTestingTimeTissuesToxic effectTransgenic OrganismsTranslatingWithdrawalcopper zinc superoxide dismutasedesignexpression vectorgain of functionin vitro Modelin vivomutantneuron apoptosisneuron lossnovelresearch study
项目摘要
DESCRIPTION (provided by applicant): In this project we will define a role for copper-zinc superoxide dismutase (SOD1) in the regulation of cell survival and death. While the wild-type (WT) SOD1 is a pro-survival protein, amyotrophic lateral sclerosis (ALS)-linked SOD1 mutants are toxic both in vitro and in vivo. We recently found that both WT and mutant SOD1 interact with the anti-apoptotic protein Bcl-2. However, the nature of the mutant SOD1 binding with Bcl-2 differs from WT SOD1. Contrary to WT SOD1, mutant SOD1 specifically localizes to spinal cord mitochondria where it forms SDS-resistant high molecular weight aggregates that bind and entrap Bcl-2. (Pasinelli et al, 2004, Neuron 43: 19-30). These studies suggest a potentially novel function for WT SOD1 in regulating cell survival and death, and a novel, toxic gain-of-function for mutant SOD1. Thus, while WT SOD1 may protect against cell death through its interaction with Bcl-2, mutant SOD1 may become toxic by aberrantly binding to Bcl-2 and converting Bcl-2 into a toxic or non-functional protein. In support of this hypothesis, we now have preliminary data indicating that both WT and mutant SOD1 might require Bcl-2 to exert their anti-and-pro apoptotic function respectively. With the present proposal we intend to characterize the anti and pro-death function of WT and mutant SOD1 and their respective interactions with Bcl-2. The ultimate goal is to understand the mechanism(s) of mutant SOD1-mediated toxicity and to define a potential role for the mitochondrial mutant SOD1/Bcl-2 complex in ALS pathogenesis. The specific aims are: 1) (A) To determine whether WT SOD1 pro-survival activity depends on its binding to Bcl-2, and (B) to determine whether mutant SOD 1-mediated toxicity depends on the aberrant interaction with Bcl-2. 2) (A) To identify the region(s) in SOD1 essential for the binding with Bcl-2, and (B) to study the difference in binding strength between WT SOD1 and Bcl-2 and mutant SOD1 and Bcl-2. 3) (A) To determine whether Bcl-2 undergoes conformational modifications upon binding with mutant SOD1 and.(B) to test the potential benefit of Bcl-2 and SOD1 like-peptides that abolish binding between Bcl-2 and mutant SOD1 on our cell culture model of mutant SOD1-linked ALS. 4) To determine whether Bcl-2 mediates mutant SOD1 mitochondrial translocation. 5) To study the correlation between mutant SOD1/Bcl-2-containing aggregates and ALS using transgenic ALS mice and patients.
描述(申请人提供):在这个项目中,我们将确定铜锌超氧化物歧化酶(SOD1)在调节细胞存活和死亡中的作用。野生型(WT)SOD1是一种促进生存的蛋白,而肌萎缩侧索硬化症(ALS)相关的SOD1突变体在体外和体内都是有毒的。我们最近发现WT和突变体SOD1都与抗凋亡蛋白Bcl-2相互作用。然而,突变体SOD1与Bcl-2结合的性质与WT SOD1不同。与WT SOD1相反,突变型SOD1特异性地定位于脊髓线粒体,在那里它形成结合和捕获Bcl-2的耐十二烷基硫酸钠的高分子量聚集体。(Pasinelli等,2004,Neuron 43:19-30)。这些研究表明,WT SOD1在调节细胞存活和死亡方面具有潜在的新功能,而突变体SOD1具有新的毒性功能。因此,虽然WT SOD1可能通过与Bcl-2的相互作用来保护细胞免受死亡,但突变的SOD1可能通过异常地与Bcl2结合并将Bcl2转化为有毒或无功能的蛋白质而变得有毒。为了支持这一假说,我们现在有初步的数据表明,WT和突变体SOD1可能分别需要Bcl-2发挥其抗和促凋亡功能。根据目前的建议,我们打算表征WT和突变体SOD1的抗死亡和促死亡功能,以及它们各自与Bcl-2的相互作用。最终目的是了解突变的Sod1介导的毒性的机制(S),并确定线粒体突变的Sod1/Bcl2复合体在ALS发病机制中的潜在作用。其具体目的是:(1)(A)确定WT SOD1的促生存活性是否取决于其与Bcl-2的结合;(B)确定突变型SOD1介导的毒性是否取决于其与Bcl-2的异常相互作用。2)(A)鉴定SOD1中与Bcl2结合所必需的区域(S);(B)研究WTSOD1Bcl一2与突变型SOD1Bcl一2结合强度的差异。3)(A)确定Bcl-2与突变型SOD1结合后是否发生构象改变,以及(B)在我们建立的突变型SOD1连锁的ALS细胞培养模型上,测试取消Bcl2和突变型SOD1结合的类似肽对细胞的潜在益处。4)确定Bcl2是否介导突变型SOD1线粒体易位。5)利用转基因ALS小鼠和患者研究突变的SOD1/Bcl2聚集体与ALS的相关性。
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)
专利数量(0)
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PIERA PASINELLI其他文献
PIERA PASINELLI的其他文献
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{{ truncateString('PIERA PASINELLI', 18)}}的其他基金
Contribution of astrocytes to mutant FUS-linked Amyotrophic Lateral Sclerosis
星形胶质细胞对突变型 FUS 相关肌萎缩侧索硬化症的影响
- 批准号:
10160975 - 财政年份:2019
- 资助金额:
$ 41.75万 - 项目类别:
Contribution of astrocytes to mutant FUS-linked Amyotrophic Lateral Sclerosis
星形胶质细胞对突变型 FUS 相关肌萎缩侧索硬化症的影响
- 批准号:
10624831 - 财政年份:2019
- 资助金额:
$ 41.75万 - 项目类别:
Contribution of astrocytes to mutant FUS-linked Amyotrophic Lateral Sclerosis
星形胶质细胞对突变型 FUS 相关肌萎缩侧索硬化症的影响
- 批准号:
10404651 - 财政年份:2019
- 资助金额:
$ 41.75万 - 项目类别:
SOD1/Bcl-2 induced mitochondrial dysfunction in FALS and SALS.
SOD1/Bcl-2 诱导 FALS 和 SALS 线粒体功能障碍。
- 批准号:
8104822 - 财政年份:2006
- 资助金额:
$ 41.75万 - 项目类别:
SOD1/Bcl-2 induced mitochondrial dysfunction in FALS and SALS.
SOD1/Bcl-2 诱导 FALS 和 SALS 线粒体功能障碍。
- 批准号:
8411141 - 财政年份:2006
- 资助金额:
$ 41.75万 - 项目类别:
SOD1/Bc1-2 Complex: A Role in Regulating Motor Neuron Cell Death
SOD1/Bc1-2 复合物:调节运动神经元细胞死亡的作用
- 批准号:
7271129 - 财政年份:2006
- 资助金额:
$ 41.75万 - 项目类别:
SOD1/Bcl-2 induced mitochondrial dysfunction in FALS and SALS.
SOD1/Bcl-2 诱导 FALS 和 SALS 线粒体功能障碍。
- 批准号:
8217128 - 财政年份:2006
- 资助金额:
$ 41.75万 - 项目类别:
SOD1/Bc1-2 Complex: A Role in Regulating Motor Neuron Cell Death
SOD1/Bc1-2 复合物:调节运动神经元细胞死亡的作用
- 批准号:
7491015 - 财政年份:2006
- 资助金额:
$ 41.75万 - 项目类别:
SOD1/Bc1-2 Complex: A Role in Regulating Motor Neuron Cell Death
SOD1/Bc1-2 复合物:调节运动神经元细胞死亡的作用
- 批准号:
7387966 - 财政年份:2006
- 资助金额:
$ 41.75万 - 项目类别:
SOD1/Bcl-2 induced mitochondrial dysfunction in FALS and SALS.
SOD1/Bcl-2 诱导 FALS 和 SALS 线粒体功能障碍。
- 批准号:
8600732 - 财政年份:2006
- 资助金额:
$ 41.75万 - 项目类别:
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