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Genetic Dissection of Mechanisms by Which Exercise Promotes Systemic Health

运动促进全身健康机制的基因剖析

基本信息

批准号：
9360536
负责人：
MONICA A. DRISCOLL
金额：
$ 38.58万
依托单位：
RUTGERS, THE STATE UNIV OF N.J.
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-09-30 至 2021-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9360536
关键词：
Acute Address Adult Age Aging Animal Testing Animals Area Behavior Biological Assay Biology Caenorhabditis elegans Cells Cellular biology Clinical Data Diabetes Mellitus Disease Disease model Dissection Exercise Exercise stress test Future Gene Expression Gene Proteins Genes Genetic Genetic Models Genetic Transcription Health Health Benefit Human Impaired cognition Individual Intervention Invertebrates Knowledge Life Longevity Pathway MAP Kinase Gene MAPK14 gene Maintenance Malignant Neoplasms Measures Mediating Medicine Methods Microfluidic Microchips Mitochondria Modeling Modern Medicine Modernization Molecular Molecular Genetics Morphology Muscle Names Nematoda Nerve Degeneration Nervous system structure Neurodegenerative Disorders Neurons Orthologous Gene Paralysed Pathway interactions Phenotype Physical activity Physiological Positioning Attribute Predisposition Proteins Recovery Rejuvenation Research Resolution Rest Role Siblings Signal Transduction Stress Structural Protein Structure Swimming Synapses System Testing Therapeutic Thermogenesis Time Tissues Touch sensation Toxic effect Training Translating Work aging brain anti aging base combat design effective therapy exercise training fly frailty functional decline genetic manipulation healthy aging immunosenescence improved in vivo innovative technologies insight interest mitochondrial dysfunction muscle strength mutant neuroprotection neurotoxic neurotoxicity novel oxidation promoter proteostasis receptor sarcopenia sedentary tool young adult

项目摘要

Regular exercise exerts a profound positive impact on health and the quality of aging. Still, our understanding of the molecular mechanisms that mediate systemic exercise benefits remains surprisingly incomplete. In particular, details of how work in muscle translates to system-wide maintenance, disease deterrence, and even rejuvenation, are too poorly understood to be harnessed for therapeutic applications. We propose to address this knowledge gap from a new angle that features innovative technology, facile gene manipulation, and integrative in vivo neuronal assays over time. We have developed a C. elegans exercise model that uniquely positions us to address three aims that together will advance understanding of the fundamental biology of exercise benefits outside of the muscle domain, with a focus on neuronal aging. Aim 1 will: a) test C. elegans homologs of genes involved in classical mammalian exercise training pathways for roles in strength adaptation, b) address potential requirements for selected stress/longevity pathway genes in exercise-induced enhancement of muscle strength; c) define animal-wide transcription changes that accompany the trained state. Work will establish a deep mechanistic framework for analysis of exercise benefits and address the degree of conservation of exercise adaptation pathways from nematodes to humans. We will firmly ground a novel genetic model in which whole-animal benefits of exercise can be dissected. In Aims 2 and 3, we shift our emphasis to address impact of exercise on neuronal healthspan. Aim 2 will define the impact of exercise on neuronal healthspan while addressing the overall hypothesis that exercise induces functional, structural, and molecular adaptations in neurons, delaying their age-associated decline. We will conduct a detailed analysis of touch receptor neurons, characterizing how exercise changes neuronal function, morphological restructuring, susceptibility to neurotoxic disease protein toxicity, and mitochondrial status over adult life. We will apply selected assays to evaluate additional neuronal types to document in unprecedented cellular detail how exercise influences in vivo nervous system aging. Aim 3 will exploit unique features of the C. elegans experimental system to dissect the tissue network via which genes needed for exercise adaptation promote muscle and neuronal health benefits. We will: a) address whether selected key genes needed for muscle training act autonomously/nonautonomously to impact neuronal healthspan, and b) test exercise-inducible genes encoding secreted proteins for roles in promoting neuronal adaptations. We will gain initial insights into the tissue-interaction circuits involved in system-wide exercise benefits and we may uncover exercise-induced drivers of neuronal healthspan. Given unequivocal evidence that exercise is the most effective anti-aging, anti-disease, pro-health intervention known in medicine, genetic dissection of exercise's maintenance capacities in native context and over time should yield new insights that guide strategies for improving human health and the quality of aging.

经常锻炼对健康和衰老质量有着深远的积极影响。然而，我们的理解