How does mitochondrial dysfunction cause neurodegeneration?

线粒体功能障碍如何导致神经退行性变？

基本信息

批准号：
8094204
负责人：
Thomas Robert Clandinin
金额：
$ 23.7万
依托单位：
STANFORD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-02-01 至 2013-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8094204
关键词：
Acute Address Adult Affect Alleles Alzheimer&apos s Disease American Amyotrophic Lateral Sclerosis Animal Model Antioxidants Behavioral Behavioral Genetics Biological Cell Differentiation process Child Childhood Chromosome Mapping Chronic Data Development Disease Disease Progression Disease model Drosophila genus Drug Delivery Systems Electron Transport Encephalopathies Exposure to Eye Genes Genetic Genetic Models Genetic Screening Genetic screening method Hereditary Disease Histological Techniques Huntington Disease Infant Lead Leigh Disease Life Link Maintenance Mammals Mediating Metabolism Mitochondria Modeling Molecular Molecular Genetics Molecular Target Mutation Nerve Degeneration Neurodegenerative Disorders Neurons Parkinson Disease Pathway interactions Pharmaceutical Preparations Photoreceptors Play Process Production Proteins Reactive Oxygen Species Relative (related person)Role Second Messenger Systems Signal Transduction Structure Synapses System Techniques Temperature Testing Work base cellular targeting drug development effective therapy fly gene function insight mitochondrial dysfunction neuronal cell body novel progressive neurodegeneration research study second messenger synaptogenesis tool treatment strategy

项目摘要

DESCRIPTION (provided by applicant): Mitochondrial dysfunction has been linked to a number of neurodegenerative diseases, including Parkinson's Disease, Alzheimer's Disease and Amyotrophic Lateral Sclerosis, among others. However, the precise role of mitochondrial dysfunction in degeneration, relative to other cellular and molecular mechanisms, remains unclear. Importantly, however, rare genetic conditions such as Leigh Disease directly affect mitochondrial function and cause neurodegeneration in infants and children. This proposal develops a novel model of Leigh Disease in the fruit fly, and uses the powerful genetic, behavioral and histological tools available in this system to probe the specific mechanisms by which mitochondrial dysfunction causes degeneration. Several alternate mechanisms, including effects on cellular metabolism, and the excessive production of reactive oxygen species (ROS) have been proposed to link alterations in mitochondrial function to neuronal degeneration. Previous work demonstrates that mitochondrial dysfunction triggers two genetically distinct degenerative processes. One of these pathways is dependent on ROS production, and leads specifically to synapse loss, while the other pathway is ROS-independent and causes degeneration of cell body structures. This proposal addresses the following questions. Do ROS activate a degeneration-inducing signal, or act as chronic damaging agents, or both? What are the molecular targets of mitochondrial dysfunction that lead to neurodegeneration? Neurodegenerative diseases afflict many people, with Parkinson's Disease alone affecting more than 1 million Americans. At present, however, treatment options for most neurodegenerative diseases are highly limited. Animal models have provided new understanding of the basic molecular mechanisms underlying specific aspects of neurodegenerative disease, and have played important roles in identifying new drug targets. By developing a new model of mitochondrial encephalopathy in the fruit fly, this proposal will contribute significantly both to our fundamental understanding of neurodegenerative disease, and will identify new proteins that regulate disease progression. PUBLIC HEALTH RELEVANCE: Neurodegenerative diseases like Parkinson's Disease, Alzheimer's Disease and Amyotrophic lateral sclerosis afflict millions of Americans, yet existing treatments are of only limited efficacy. This proposal develops a new animal model of neurodegenerative disease, and uses genetic and molecular biological techniques to define novel mechanisms affecting disease progression. These studies will provide new targets for drug development, and will broadly inform treatment strategies.

描述（由申请人提供）：线粒体功能障碍与许多神经退行性疾病有关，包括帕金森氏病，阿尔茨海默氏病和肌萎缩性侧面硬化症等。然而，相对于其他细胞和分子机制，线粒体功能障碍在变性中的确切作用尚不清楚。然而，重要的是，诸如Leigh疾病之类的罕见遗传条件直接影响线粒体功能，并导致婴儿和儿童的神经变性。该提案在果蝇中开发了一种新型的Leigh疾病模型，并使用该系统中可用的强大遗传，行为和组织学工具来探测线粒体功能障碍引起变性的特定机制。已经提出了几种替代机制，包括对细胞代谢的影响以及活性氧（ROS）的过量产生，以将线粒体功能的改变与神经元变性联系起来。先前的工作表明，线粒体功能障碍会触发两个遗传上不同的退化过程。这些途径之一取决于ROS的产生，并专门导致突触损失，而另一种途径则是不依赖ROS的，并导致细胞体结构的变性。该提案解决了以下问题。 ROS会激活诱导变性的信号，还是充当慢性损害药物，或两者兼而有之？线粒体功能障碍导致神经变性的分子靶标是什么？神经退行性疾病困扰着许多人，仅帕金森氏病就会影响超过100万美国人。然而，目前，大多数神经退行性疾病的治疗方案受到高度限制。动物模型对神经退行性疾病的特定方面的基本分子机制提供了新的了解，并在识别新药物靶标方面发挥了重要作用。通过在果蝇中开发一种新的线粒体脑病模型，该提案将对我们对神经退行性疾病的基本理解产生重大贡献，并将确定调节疾病进展的新蛋白质。公共卫生相关性：神经退行性疾病，例如帕金森氏病，阿尔茨海默氏病和肌萎缩性的侧面硬化症折磨数百万美国人，但现有治疗只有有限的疗效。该建议开发了一种新的神经退行性疾病动物模型，并使用遗传和分子生物技术来定义影响疾病进展的新机制。这些研究将为药物开发提供新的目标，并将广泛为治疗策略提供信息。