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: 8279369
• 负责人: Carlos Torres Moraes
• 金额: $ 30.15万
• 依托单位: UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 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: https://reporter.nih.gov/project-details/8279369
• 关键词: Age; Aging; Biogenesis; DNA Restriction Enzymes; DNA polymerase gamma; Data; Defect; Double Strand Break Repair; Generations; Genetic Recombination; Goals; Kinetics; Laboratories; Lead; Life; Mitochondria; Mitochondrial DNA; Modeling; Molecular; Mus; Muscle; Nerve Degeneration; Oxidative Phosphorylation; Play; Polymerase; Process; Publishing; Reading; Role; Skeletal Muscle; Testing; Time; Tissues; age related; age related neurodegeneration; aging brain; base; mitochondrial dysfunction; mouse model; normal aging; novel; novel strategies; protective effect; public health relevance

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）：生命中线粒体氧化磷酸化功能的逐渐下降可能是导致神经变性的原因。但是，对线粒体缺陷所涉及的机制的理解仍然是基本和实际方法来减轻此问题的方法。 我们的项目将研究线粒体参与神经变性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。 我们将使用一种在实验室中开发的新型小鼠，其中线粒体靶向限制性核酸内切酶（Mito-PSTI）以组织特异性且可诱导的方式表达。 Mito-PSTI引起的双链破裂导致重组和缺失形成。我们将在中枢神经系统或普遍存在的中枢神经系统中产生mtDNA缺失。线粒体聚合酶γ在修复这些双链断裂中的作用也将进行分析。该目标的目的是研究在神经退行性和衰老过程中积累不同水平的mtDNA缺失的功能后果。在该提案的第二部分中，我们将通过在骨骼肌或普遍存在的PGC-1A表达来增加PGC-1A的表达来开发方法来减轻CNS和其他组织的衰老。这将通过稳定和诱导的表达来实现。 PGC-1A的效果将在正常衰老小鼠和校对缺陷的聚合酶γ“突变器小鼠”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发布和未发表的初步数据。 我们相信，这两个目标的实现不仅会更好地理解与年龄相关的神经变性中线粒体缺陷的作用，而且还可以采取新颖的方法来抵消这些效果。 公共卫生相关性：据信线粒体在神经变性和衰老中起主要作用。通过更好地理解此过程中涉及的机制，并通过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作用。