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

基本信息

批准号：
8359960
负责人：
Carlos Torres Moraes
金额：
$ 33.47万
依托单位：
UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-05-15 至 2017-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8359960
关键词：
Ablation Address Affect Agonist Alleles Atrophic Behavioral Biochemical Pathway Biogenesis Biology Brain Brain region Clinical Complex Corpus striatum structure Cultured Cells Data Defect Disease Encephalopathies Genes Genotype Goals Hippocampus (Brain)Knock-out Laboratories Learning Leigh Disease Lipids Longevity Metabolic Metabolic Diseases Mitochondria Mitochondrial Diseases Modeling Molecular Molecular Profiling Multienzyme Complexes Mus Muscle Myoclonic Epilepsies NADH dehydrogenase (ubiquinone)Neurodegenerative Disorders Neurons Optic Nerve Oxidative Phosphorylation PPAR Pathway Pathogenesis Peroxisome Proliferator-Activated Receptors Phenotype Play Population Predisposition Production Respiratory Chain Retinal Diseases Role Screening procedure Sensorineural Hearing Loss Stroke System Testing Therapeutic Variant Work age related base design effective therapy information gathering mouse model oxidation oxidative damage protective effect recombinase respiratory therapy development tool treatment strategy

项目摘要

DESCRIPTION (provided by applicant): Defects in the mitochondrial respiratory complexes cause a number of metabolic diseases and are believed to play pivotal roles in the pathogenesis of age-related neurodegenerative disorders. Our laboratory's long term goal is to understand the biology of these conditions and develop effective treatments. To achieve these goals we have developed mouse models with defects in different mitochondrial respiratory complexes. We now propose to study the pathogenic mechanisms associated with defects in specific mitochondrial respiratory complexes (complexes I, III or IV). Our preliminary data showed some remarkable differences in the phenotypes depending on the complex affected. The identification of metabolic signatures of brains affected by the different defects will be used to better understand the pathogenic mechanisms. Finally, based on the information gathered in the first two aims, we will test whether increases in mitochondrial biogenesis and lipid utilization can have a protective effect for certain mitochondrial encephalopathies. PUBLIC HEALTH RELEVANCE: Defects in mitochondrial respiratory complexes have been associated with many metabolic diseases. There is a great deal of variation in the clinical manifestations of these defects, but the reason for this is not known. We propose to study mouse models with defects in the respiratory complexes I, III and IV to better define the mechanisms responsible for the different clinical presentations. We will define metabolic signatures of deficient brains and use this information to fine tune therapeutic approaches based on an increase in mitochondrial biogenesis.

描述（由申请人提供）：线粒体呼吸复合体的缺陷会引起许多代谢疾病，并被认为在与年龄相关的神经退行性疾病的发病机制中发挥关键作用。我们实验室的长期目标是了解这些病症的生物学原理并开发有效的治疗方法。为了实现这些目标，我们开发了具有不同线粒体呼吸复合物缺陷的小鼠模型。我们现在建议研究与特定线粒体呼吸复合物（复合物 I、III 或 IV）缺陷相关的致病机制。我们的初步数据显示，根据受影响的复合体，表型存在一些显着差异。受不同缺陷影响的大脑代谢特征的识别将用于更好地了解致病机制。最后，根据前两个目标收集的信息，我们将测试线粒体生物发生和脂质利用的增加是否可以对某些线粒体脑病产生保护作用。公共卫生相关性：线粒体呼吸复合体的缺陷与许多代谢疾病有关。这些缺陷的临床表现存在很大差异，但其原因尚不清楚。我们建议研究具有呼吸复合体 I、III 和 IV 缺陷的小鼠模型，以更好地确定导致不同临床表现的机制。我们将定义缺陷大脑的代谢特征，并利用这些信息根据线粒体生物发生的增加来微调治疗方法。