Pharmacologic treatment of mitochondrial complex I dysfunction in C. elegans

线虫线粒体复合物 I 功能障碍的药物治疗

基本信息

批准号：
8302322
负责人：
MARNI J FALK
金额：
$ 39.9万
依托单位：
CHILDREN'S HOSP OF PHILADELPHIA
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-09-27 至 2015-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8302322
关键词：
Acetylcysteine Adult Affect Age Agmatine Amino Acids Animal Model Animals Antioxidants Arginine Attenuated Biochemical Bioinformatics Biological Caenorhabditis elegans Carnitine Citric Acid Cycle Clinical Coenzyme Q10 Complex Creatine Development Diagnosis Disease Dose Drug Prescriptions Ethnic Origin Evaluation Fenofibrate Fluorescence Microscopy Functional disorder Gases Genes Genetic Genetic Models Goals Hereditary Disease Human Hydroxybutyrates Impairment Individual Leucovorin Life Longevity Mammals Mediating Membrane Potentials Metabolic Metabolic Pathway Microarray Analysis Mitochondria Mitochondrial Diseases Modeling Molecular Profiling Nematoda Nicotinic Acids Organ failure Organism Oxidants Pathway interactions Patients Peroxisome Proliferator-Activated Receptors Pharmaceutical Preparations Phenotype Physiological Prevalence Probucol RNA Interference Relative (related person)Respiratory Chain Resveratrol Signal Pathway Subgroup Symptoms System Therapeutic Thiamine Thioctic Acid Translational Research Vitamin E Vitamins Work base cost effective therapy feeding in vivo mitochondrial membrane mutant new therapeutic target orotate oxidant stress public health relevance response rosiglitazone sirtinol stable isotope therapeutic target

项目摘要

DESCRIPTION (provided by applicant): Dysfunction of complex I in the mitochondrial respiratory chain (RC) underlies an astonishingly frequent group of multi-systemic disorders that afflict all ages and ethnicities. A relative inability to objectively assess cellular mechanisms that mediate widely variable disease manifestations has largely prohibited evaluation and implementation of effective therapies in affected patients. We hypothesize that pharmacologic modulation of the cellular consequences of mitochondrial RC dysfunction will offer effective therapies for common subgroups of RC dysfunction, irrespective of individual pathogenic cause. The overall goal of this proposal is to elucidate mechanisms by which pharmacologic agents modulate the metabolic consequences of RC dysfunction, capitalizing on the inherent investigative advantages that the C. elegans animal model provides. The Specific Aims of this proposal are to: SA1: Determine whether pharmacologic modulation of the PPAR/SIRT1 pathway in C. elegans will attenuate, or even reverse, the metabolic consequences of complex I dysfunction; and SA2: Characterize in vivo consequences of "mitochondrial cocktail" components in a translational C. elegans animal model of complex I dysfunction. Five pharmacologic agents that directly modulate PPAR/SIRT1-related signaling pathways as well as fifteen common "mitochondrial cocktail" components in four major classes (vitamins, antioxidants, complex I post- translational activator, and intermediary metabolic modifiers) will be studied in RC complex I mutants in SA1 and SA2, respectively. Bioinformatics integration will be performed to discern the overall efficacy of each pharmacologic agent on 5 in vivo phenotypes for both aims: (a) lifespan; (b) metabolic pathway profiling by expression microarray analysis; (c) flux through intermediary metabolic pathways using stable isotopes; (d) mitochondrial membrane potential by fluorescence microscopy; and (e) relative mitochondrial oxidant burden by fluorescence microscopy. Mechanisms underlying discernible phenotypic responses will be explored by in vivo functional analyses in complex I mutants harboring RNA interference-induced knockdown for individual PPAR/SIRT1 pathway genes. In this manner, drugs having postulated benefit for human RC disease that currently lack scientific or clinical evidence of either efficacy or harm can be objectively and non- invasively screened in a low-cost and high-throughput fashion in C. elegans. This translational research may suggest specific therapeutic targets and potentially effective pharmacologic agents to mitigate the global sequelae of human mitochondrial disease. PUBLIC HEALTH RELEVANCE: Mitochondrial complex I dysfunction occurs in an astonishingly frequent, varied, and largely untreatable group of genetic disorders afflicting all ages and ethnicities. Caenorhabditis elegans offers a robust genetic model in which to assess the global impact of complex I dysfunction and therapeutic candidates. This translational research may demonstrate effective pharmacologic therapies, and their specific mechanisms, to potentially mitigate the secondary consequences of human mitochondrial disease.

描述（由申请人提供）：线粒体呼吸链中复合物I的功能障碍（RC）是一组惊人的多系统疾病群体，使所有年龄和种族都困扰着。相对无法客观地评估介导广泛可变疾病表现的细胞机制，在很大程度上禁止评估和实施受影响患者的有效疗法。我们假设线粒体RC功能障碍的细胞后果的药理调节将为RC功能障碍的常见亚组提供有效的疗法，而与个人致病性原因无关。该提案的总体目标是阐明药理剂调节RC功能障碍的代谢后果的机制，并利用秀丽隐杆线虫动物模型提供的固有的调查优势。该提案的具体目的是：SA1：确定秀丽隐杆线虫中PPAR/SIRT1途径的药理调制是否会衰减，甚至会逆转复合I功能障碍的代谢后果；和SA2：表征“线粒体鸡尾酒”成分的体内后果，在复杂I功能障碍的秀丽隐杆线虫模型中。五种直接调节PPAR/SIRT1相关信号途径的药理学剂以及四个主要类别（维生素，抗氧化剂，复杂的I抗转化激活剂，复杂的I抗氧化剂，抗氧化剂，抗转化激活剂和中间代谢修饰符）的15个常见的“线粒体鸡尾酒”组件将在RC In Complex In Mutants In sa1和Sa1和Sa2中的SA2和SA2中都进行研究。将进行生物信息学的整合，以辨别每种药物剂在5个体内表型上的总体疗效，这两个目的是：（a）寿命；（b）通过表达微阵列分析进行代谢途径分析；（c）使用稳定同位素通过中间代谢途径的通量；（d）通过荧光显微镜进行线粒体膜电位；（E）通过荧光显微镜进行相对的线粒体氧化剂负担。在具有RNA干扰诱导的单个PPAR/SIRT1途径基因的RNA干扰诱导的敲低的复合物I突变体中，将探索可辨别表型反应的机制。以这种方式，当前缺乏疗效或伤害的科学或临床证据的人类RC疾病的药物可以客观和非侵入性地以秀丽隐杆线虫的低成本和高通量方式进行筛查。这项翻译研究可能表明特定的治疗靶标和潜在有效的药理学剂来减轻人类线粒体疾病的全球后遗症。公共卫生相关性：线粒体复合物I功能障碍发生在一个惊人的频繁，多样化且在很大程度上不可治疗的遗传疾病群体中，困扰着所有年龄和种族。秀丽隐杆线虫提供了一种强大的遗传模型，可以在其中评估复杂I功能障碍和治疗候选者的全球影响。这项翻译研究可能表明有效的药理疗法及其特定机制，可以减轻人类线粒体疾病的次要后果。