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Determination of circulation factors that mediate the health benefits of exercise in mitochondrial aging

确定调节运动对线粒体衰老健康益处的循环因素

基本信息

批准号：
10011425
负责人：
TOMAS ALBERTO PROLLA
金额：
$ 25.21万
依托单位：
CYTEGEN CORPORATION
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-15 至 2022-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10011425
关键词：
Affect Age Aging Alzheimer&apos s Disease Automobile Driving Biochemical Biological Assay Blood Circulation Cells Complement DNA biosynthesis Data Defect Disease Disease Progression Endogenous Factors Engineering Excision Exercise Exonuclease Fractionation Functional disorder Funding Future Genes Genomics Goals Growth Health Benefit Hereditary Disease Human Impairment Individual Injections Knock-in Laboratories Lead Longevity Measurement Mediating Metabolic Mitochondria Mitochondrial DNA Mitochondrial Diseases Mitochondrial Proteins Modeling Mus Muscle Muscle function Mutant Strains Mice Mutation Myocardium Nerve Degeneration Neurodegenerative Disorders Neuromuscular Diseases Parkinson Disease Phase Phenotype Physiological Plasma Polymerase Premature aging syndrome Preparation Property Proteins Proteomics Protocols documentation Resolution Respiration Role Schedule Skeletal Muscle Syndrome Testing Tissues Translating Work age related base early onset effective therapy endurance exercise exercise training heart function human disease improved mitochondrial dysfunction mitochondrial fitness mouse model mutant normal aging novel novel therapeutic intervention phase II trial preclinical study premature research clinical testing sedentary small molecule

项目摘要

Project Summary/Abstract: This proposal seeks to test the hypothesis that endurance exercise stimulates the release of circulating factors that improve mitochondrial fitness. CyteGen’s goal is to identify these endogenous factors and engineer them to treat diseases in which mitochondrial dysfunction is central. These diseases include neurodegenerative and other diseases associated with aging, as well as the rare mitochondrial diseases that arise from inborn errors in genes encoding mitochondrial proteins that affect 1 in 5000 individuals. Currently, no effective treatments are available. To identify factors that improve mitochondrial fitness, CyteGen is using a unique mouse model, created by the PI. This model displays a profound mitochondrial syndrome with reduced life span and premature aging due to impaired exonuclease proofreading activity of POLG, the sole mtDNA polymerase. POLG is highly conserved between mice and humans and over 200 mutations in this polymerase have been associated with human disease, supporting CyteGen’s contention that mouse discoveries will translate into humans. Endurance exercise of POLG mutant mice reverses the early-onset aging syndrome by overcoming the POLG defect in mitochondrial function. Analyses of tissues in exercised mice suggests that endogenous circulating factors may be responsible. We will test the hypothesis that circulating factors secreted as a result of exercise improve mitochondrial function by collecting plasma from exercised POLG mice and sedentary controls and injecting it into old POLG mice that display reduced mitochondrial function and impaired skeletal muscle and cardiac function. Following a schedule of injections that mimics exercise training, we will examine metabolic capacity, cardiac function, spontaneous activity levels and mitochondrial function. A second aim of this study is to use cell based models to determine the effects of plasma from exercised mice on mitochondrial function of POLG mutant cells. The goal of our studies is to identify circulating factors that reverse mitochondrial dysfunction with suitable properties to support initiation of preclinical studies in preparation for clinical evaluation.

项目总结/文摘: