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
• 负责人: Carlos Torres Moraes
• 金额: $ 43.88万
• 依托单位: UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-05-15 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9912858
• 关键词: Affect; Alanine-Specific tRNA; Brain; Breeding; Cells; Collaborations; DNA; DNA Restriction Enzymes; Defect; Deletion Mutation; Disease; Enzymes; Generations; Genes; Glutamates; Institutes; Mitochondria; Mitochondrial DNA; Mitochondrial Diseases; Modeling; Molecular; Mus; Muscle; Mutation; Nerve Degeneration; Neuraxis; Neurodegenerative Disorders; Neurons; Nuclear; Oxidative Phosphorylation; Pathogenicity; Phenotype; Point Mutation; Population; Predisposition; Respiratory Chain; Role; Testing; Transfer RNA; age related neurodegeneration; in vivo; mitochondrial DNA mutation; mitochondrial dysfunction; mouse model; mutant; novel

Defects in mitochondrial oxidative phosphorylation (OXPHOS) have been associated with various primary mitochondrial diseases as well as with neurodegenerative disorders. Such disorders can be caused by defects in nuclear or mitochondrial DNA (mtDNA). We propose to take advantage of existing and new mouse models created in our lab to manipulate the mtDNA to study fundamental mechanisms of the role of mtDNA mutations in neurodegeneration. We will also use DNA editing enzymes to further modulate mtDNA heteroplasmy in vivo. We will analyze the ability of different neuronal types (glutamatergic and dopaminergic) to accumulate mtDNA deletions (aim#1) and a pathogenic point mutation in a tRNA gene (aim#2). With these models in place, we will also study the susceptibility of glutamatergic and dopaminergic neuronal subtypes to OXPHOS defects.

线粒体氧化磷酸化（OXPHOS）的缺陷已与各种原代相关 线粒体疾病以及神经退行性疾病。这种疾病可能是由缺陷引起的 核或线粒体DNA（mtDNA）。我们建议利用现有的和新的鼠标模型 在我们的实验室中创建以操纵mtDNA来研究mtDNA作用的基本机制 神经退行性中的突变。我们还将使用DNA编辑酶进一步调节mtDNA 体内异质。我们将分析不同神经元类型（谷氨酸能和多巴胺能）的能力 积累mtDNA缺失（AIM＃1）和tRNA基因中的致病点突变（AIM＃2）。与这些 模型还适当，我们还将研究谷氨酸能和多巴胺能神经元亚型对 Oxphos缺陷。