Mitochondrial Dysfunction in Neurodegeneration and Compensatory Approaches
神经退行性变中的线粒体功能障碍和补偿方法
基本信息
- 批准号:8076189
- 负责人:
- 金额:$ 30.15万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2010
- 资助国家:美国
- 起止时间:2010-06-01 至 2015-05-31
- 项目状态:已结题
- 来源:
- 关键词:AgeAgingBiogenesisDNA Restriction EnzymesDNA polymerase gammaDataDefectDouble Strand Break RepairGenerationsGenetic RecombinationGoalsKineticsLaboratoriesLeadLifeMitochondriaMitochondrial DNAModelingMolecularMusMuscleNerve DegenerationOxidative PhosphorylationPlayPolymeraseProcessPublishingReadingRoleSkeletal MuscleTestingTimeTissuesage relatedage related neurodegenerationaging brainbasemitochondrial dysfunctionmouse modelnormal agingnovelnovel strategiesprotective effectpublic health relevance
项目摘要
DESCRIPTION (provided by applicant): A progressive decline in mitochondrial oxidative phosphorylation function during life is a likely contributor to neurodegeneration. However, the understanding of the mechanisms involved in the mitochondrial defects is still rudimentary and practical approaches to mitigate this problem are not available. Our project will study these two aspects of mitochondrial involvement in neurodegeneration and aging. In the first part, we propose to study the role of mitochondrial DNA (mtDNA) deletions in the aging of the brain. We will use a novel mouse developed in our laboratory in which a mitochondria targeted restriction endonuclease (Mito-PstI) is expressed in a tissue-specific and inducible fashion. The double-strand breaks elicited by Mito-PstI lead to recombination and deletion formation. We will generate mtDNA deletions in the CNS or ubiquitously. The role of the mitochondrial polymerase gamma in repairing these double-strand breaks will also be analyzed. The goal of this aim is to study the functional consequences of accumulating different levels of mtDNA deletions during neurodegeneration and aging. In the second part of the proposal, we will develop approaches to mitigate the aging of CNS and other tissues by increasing the expression of PGC-1a, either in skeletal muscle or ubiquitously. This will be achieved by stable and inducible expression. The effect of PGC-1a will be tested both in normal aging mice and in the proof-reading deficient polymerase gamma "mutator mouse". The latter is a model of accelerated aging. Both aims are based on extensive published and unpublished preliminary data. We are confident that the accomplishment of these two aims will lead to not only a better understanding of the role of mitochondrial defects in age-related neurodegeneration but also to novel approaches to counteract these effects.
PUBLIC HEALTH RELEVANCE: Mitochondria is believed to play a major role in neurodegeneration and aging. By better understanding the mechanisms involved in this process and by developing approaches to counteract these effects, the debilitating effects of the neurodegenerative process could be mitigated.
描述(由申请人提供):生命期间线粒体氧化磷酸化功能的逐渐下降可能是神经变性的一个原因。然而,对线粒体缺陷所涉及机制的理解仍然处于初级阶段,并且还没有缓解这一问题的实用方法。 我们的项目将研究线粒体参与神经退行性变和衰老的这两个方面。在第一部分中,我们建议研究线粒体 DNA (mtDNA) 缺失在大脑衰老中的作用。 我们将使用我们实验室开发的新型小鼠,其中线粒体靶向限制性内切酶 (Mito-PstI) 以组织特异性和可诱导的方式表达。 Mito-PstI 引起的双链断裂导致重组和缺失形成。我们将在中枢神经系统或无处不在产生线粒体DNA缺失。还将分析线粒体聚合酶 γ 在修复这些双链断裂中的作用。这一目标的目的是研究神经退行性变和衰老过程中不同水平 mtDNA 缺失积累的功能后果。在该提案的第二部分,我们将开发通过增加骨骼肌中或无处不在的 PGC-1a 表达来减轻中枢神经系统和其他组织衰老的方法。这将通过稳定且可诱导的表达来实现。 PGC-1a 的效果将在正常衰老小鼠和校对缺陷聚合酶 γ“突变小鼠”中进行测试。后者是加速衰老的模型。这两个目标均基于广泛的已发表和未发表的初步数据。 我们相信,这两个目标的实现不仅将导致人们更好地了解线粒体缺陷在与年龄相关的神经变性中的作用,而且还将带来抵消这些影响的新方法。
公共卫生相关性:线粒体被认为在神经退行性变和衰老中发挥着重要作用。通过更好地理解这一过程中涉及的机制并开发抵消这些影响的方法,可以减轻神经退行性过程的衰弱影响。
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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Carlos Torres Moraes其他文献
Carlos Torres Moraes的其他文献
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{{ truncateString('Carlos Torres Moraes', 18)}}的其他基金
Cellular and Molecular Consequences of Respiratory Chain Defects in Neurons
神经元呼吸链缺陷的细胞和分子后果
- 批准号:
8606272 - 财政年份:2012
- 资助金额:
$ 30.15万 - 项目类别:
Cellular and Molecular Consequences of Respiratory Chain Defects in Neurons
神经元呼吸链缺陷的细胞和分子后果
- 批准号:
9912858 - 财政年份:2012
- 资助金额:
$ 30.15万 - 项目类别:
Cellular and Molecular Consequences of Respiratory Chain Defects in Neurons
神经元呼吸链缺陷的细胞和分子后果
- 批准号:
8890318 - 财政年份:2012
- 资助金额:
$ 30.15万 - 项目类别:
Cellular and Molecular Consequences of Respiratory Chain Defects in Neurons
神经元呼吸链缺陷的细胞和分子后果
- 批准号:
10654889 - 财政年份:2012
- 资助金额:
$ 30.15万 - 项目类别:
Cellular and Molecular Consequences of Respiratory Chain Defects in Neurons
神经元呼吸链缺陷的细胞和分子后果
- 批准号:
8468020 - 财政年份:2012
- 资助金额:
$ 30.15万 - 项目类别:
Cellular and Molecular Consequences of Respiratory Chain Defects in Neurons
神经元呼吸链缺陷的细胞和分子后果
- 批准号:
8998622 - 财政年份:2012
- 资助金额:
$ 30.15万 - 项目类别:
Cellular and Molecular Consequences of Respiratory Chain Defects in Neurons
神经元呼吸链缺陷的细胞和分子后果
- 批准号:
10680366 - 财政年份:2012
- 资助金额:
$ 30.15万 - 项目类别:
Cellular and Molecular Consequences of Respiratory Chain Defects in Neurons
神经元呼吸链缺陷的细胞和分子后果
- 批准号:
8359960 - 财政年份:2012
- 资助金额:
$ 30.15万 - 项目类别:
Cellular and Molecular Consequences of Respiratory Chain Defects in Neurons
神经元呼吸链缺陷的细胞和分子后果
- 批准号:
10390458 - 财政年份:2012
- 资助金额:
$ 30.15万 - 项目类别:
Mitochondrial Dysfunction in Neurodegeneration and Compensatory Approaches
神经退行性变中的线粒体功能障碍和补偿方法
- 批准号:
8667385 - 财政年份:2010
- 资助金额:
$ 30.15万 - 项目类别:
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