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Mechanisms of Mitochondrial Myopathy

线粒体肌病的机制

基本信息

批准号：
8658209
负责人：
Andres Hernandez
金额：
$ 0.79万
依托单位：
KAROLINSKA INSTITUTE
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：
2011-04-01 至 2014-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8658209
关键词：
Affect Basic Science Biopsy Buffers Calcium Calsequestrin Cell Death Cell physiology Clinical Research Complex Data Defect Development Disease Disease Progression Disease model Functional disorder Gene Mutation Goals Human Individual Intervention Investigation Knock-out Laboratories Lead Measures Messenger RNA Mitochondria Mitochondrial DNA Mitochondrial Diseases Mitochondrial Myopathies Modeling Mus Muscle Muscle Fibers Muscle Weakness Muscle function Myopathy Organ Outcome Pathologic Processes Patients Pharmacological Treatment Play Pore Proteins Process Proteins Quality of life Respiratory Chain Rest Sampling Sarcoplasmic Reticulum Skeletal Muscle Terminally Ill Testing base design effective therapy human disease improved inhibitor/antagonist knowledge base mitochondrial dysfunction mitochondrial permeability transition pore mouse model mtTF1 transcription factor novel protein expression public health relevance research study translational approach treatment strategy uptake

项目摘要

DESCRIPTION (provided by applicant): Mitochondrial myopathies are diseases related to dysfunction of the mitochondrial respiratory chain. Defective muscle function is common in mitochondrial disorders and at present effective treatment is lacking. While the knowledge base about genetic mutations as a cause for mitochondrial myopathies is increasing, little is known about how mitochondrial dysfunction actually leads to impaired muscle function. Elucidation of these causative mechanisms will assist in the development of pharmacological treatment that could increase the quality of life of individuals with these diseases. The ultimate goal of this project is to improve the treatment of mitochondrial myopathies and, in the longer perspective, also treatment of defects in other organs affected by human mitochondrial dysfunction. Preliminary data indicate that changes in intracellular calcium (Ca2+) handling play a key role in the contractile dysfunction, and a novel way to treat these diseases has been postulated. Three Specific Aims will be used to study the mechanisms underlying the defective muscle function in mitochondrial disorders in specifically designed mouse models and in human muscle biopsies supplied to the host laboratory: 1) Examine global Ca2+ handling and force in isolated skeletal muscle cells of mouse models of mitochondrial myopathy and their controls. Measure the expression of Ca2+ handling proteins in mouse disease models and their controls. Proteins identified as altered by disease will then be examined in muscle biopsies from patients with mitochondrial myopathies. 2) Examine the changes in mitochondrial Ca2+ uptake in models of mitochondrial myopathy and their relation to opening of the mitochondrial permeability transition pore (MPTP). Identify MPTP proteins modified by disease in mouse models and subsequently investigate human samples for the same alterations. 3) Determine whether disease progression can be halted and muscle function recovered by pharmacological inhibition of mitochondrial Ca2+ uptake in mouse models. This translational approach between mouse models and human mitochondrial myopathy patients will lead to a better understanding of factors that impair contractile function and open up new strategies for treatment. PUBLIC HEALTH RELEVANCE: Defective muscle function is common in people with mitochondrial myopathies. While the knowledge base about genetic mutations as a cause for mitochondrial myopathies is increasing, little is known about how mitochondrial dysfunction actually leads to impaired muscle function. The proposed project aims to elucidate causative mechanisms and to assist in the development of pharmacological treatment that could increase the quality of life of individuals with these diseases.