线粒体功能障碍和进行性脑肌病-猫眼课题宝

线粒体功能障碍和进行性脑肌病

批准号：

7686654

负责人：

Michael John Palladino

金额：

$37.88万

依托单位：

UNIVERSITY OF PITTSBURGH AT PITTSBURGH

依托单位国家：

美国

项目类别：

财政年份：

2009

资助国家：

美国

项目状态：

已结题

起止时间：

2009-09-15 至 2011-08-31

来源：

https://reporter.nih.gov/project-details/7686654

关键词：

ATP Synthesis Pathway ATP phosphohydrolase Affect Age Animal Disease Models Animal Model Animals Antioxidants Apoptosis Ataxia Bilateral Bioenergetics Biological Biological Models Catalysis Cell Death Cells Chronic Complement Complex Corpus striatum structure Couples Data Defect Dimensions Disease Drosophila genus Event Exhibits Financial compensation Fingerprint Genes Genetic Genome Glycolysis Human Impairment In Situ Individual Inherited Ion Channel Ion Transport Leigh Disease Life Maintenance Measures Mediating Membrane Potentials Methods Missense Mutation Mitochondria Mitochondrial Diseases Mitochondrial Encephalomyopathies Mitochondrial Proteins Modeling Morphology Movement Muscle Muscle Mitochondria Mutation Necrosis Neurologic Neuropathy Organelles Oxidative Stress Pathogenesis Pathology Peptides Pharmacotherapy Phenotype Phosphocreatine Physiological Primary Cell Cultures Proteins Protons Respiration Retinitis Pigmentosa Role Sampling Specificity Structure Symptoms Syndrome System TdT-Mediated dUTP Nick End Labeling Assay Techniques Testing Tissues Transgenic Organisms Transmission Electron Microscopy age related antioxidant therapy base gel electrophoresis in vivo loss of function mutation mitochondrial dysfunction mitochondrial membrane mutant neuromuscular oligomycin sensitivity-conferring protein overexpression oxidative damage parkin gene/protein protein aminoacid sequence protein expression protein function public health relevance response

中文摘要

翻译

描述(申请人提供)：ATP6蛋白作为氢离子通道，将离子传输与旋转的ATP催化相结合。人类ATP6基因的错义突变被认为至少会导致三种以进行性肌肉损伤和神经系统症状为特征的相关和破坏性的综合征：NARP(神经病、共济失调和视网膜色素变性)、MILS(母系遗传性Leigh综合征)和FBSN(家族性双侧纹状体坏死)，并与其他几种与年龄相关的疾病的发病机制有关。我们分离了果蝇线粒体ATP6基因中的一个错义突变，并将其发展为线粒体脑肌病模型。我们建议利用这一遗传动物模型系统在体内阐明进行性脑肌病的病理生理学基础。公共卫生相关性：线粒体疾病影响到4000人中的1人。目前还没有有效的药物疗法来治疗这些毁灭性的疾病。我们对这些进行性疾病的发病机制的了解有限，很大程度上是因为缺乏这些疾病的动物模型。我们的模型系统在一个顺从的遗传系统中捕获了这些疾病的许多相关特征，本提案旨在研究这些疾病的发病机制。

英文摘要

DESCRIPTION (provided by applicant): The ATP6 protein functions as a hydrogen ion channel that couples ion transport with rotary ATP catalysis. Missense mutations in the human ATP6 gene are believed to cause at least three related and devastating syndromes characterized by progressive muscle impairment and neurological symptoms: NARP (neuropathy, ataxia, and retinitis pigmentosa), MILS (maternally inherited Leigh's syndrome) and FBSN (familial bilateral striatal necrosis) and contribute to the pathogenesis of several other age-related diseases. We have isolated a missense mutation within the mitochondrial ATP6 gene of Drosophila and developed this as model of mitochondrial encephalomyopathy. We propose to utilize this genetic animal model system to elucidate the pathophysiological basis for progressive encephalomyopathies in vivo. PUBLIC HEALTH RELEVANCE: Mitochondrial disease affect ~ 1 in 4000 individuals. Currently there exists no effective pharmacotherapy for these devastating diseases. Our understanding of disease pathogenesis of these progressive conditions is limited, in large part due to a lack of animal models of these diseases. Our model system captures many relevant features of these diseases in an amenable genetic system and this proposal aims to study pathogenesis of these diseases.

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