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.

定期锻炼对健康和衰老质量产生深远的积极影响。尽管如此，我们的理解令人惊讶的是，介导全身运动益处的分子机制仍然不完整。在特别是关于肌肉工作如何转化为全系统维护、疾病预防甚至恢复活力，人们对它知之甚少，无法用于治疗应用。我们建议解决从一个新的角度弥补这一知识差距，其特点是创新技术、简单的基因操作和随着时间的推移进行体内神经元综合分析。我们开发了一种线虫运动模型，该模型具有独特的使我们能够实现三个目标，这三个目标共同将增进对生物体基本生物学的理解运动对肌肉领域之外也有好处，重点是神经元衰老。目标 1 将：a) 测试参与经典哺乳动物运动训练途径的线虫基因同源物对于力量适应中的作用，b）解决选定的压力/长寿途径基因的潜在需求运动引起的肌肉力量增强； c) 定义动物范围内的转录变化陪伴受过训练的状态。工作将为运动分析建立一个深层的机制框架益处并解决从线虫到人类的运动适应途径的保守程度。我们将坚定地建立一种新的遗传模型，在该模型中可以剖析运动对整个动物的益处。在目标 2 和 3 中，我们将重点转向解决运动对神经元健康寿命的影响。目标 2 将定义运动对神经元健康寿命的影响，同时解决以下总体假设：运动会诱导神经元的功能、结构和分子适应，从而延缓其与年龄相关的变化衰退。我们将对触觉感受器神经元进行详细分析，描述运动如何变化神经元功能、形态重建、对神经毒性疾病的易感性、蛋白质毒性，以及成年生活中的线粒体状态。我们将应用选定的检测来评估其他神经元类型以前所未有的细胞细节记录运动如何影响体内神经系统衰老。目标 3 将利用线虫实验系统的独特功能来剖析组织网络，通过该网络运动适应所需的基因可促进肌肉和神经元的健康益处。我们将：a) 解决肌肉训练所需的选定关键基因是否自主/非自主地发挥作用以产生影响神经元健康寿命，b) 测试编码分泌蛋白的运动诱导基因在促进神经元健康方面的作用神经元的适应。我们将对全系统涉及的组织相互作用回路有初步的了解运动的好处，我们可能会发现运动引起的神经元健康寿命的驱动因素。有明确证据表明运动是最有效的抗衰老、抗疾病、有利于健康的干预措施医学上已知，对运动在自然环境下和随着时间的推移维持能力进行基因剖析应该产生新的见解，指导改善人类健康和老龄化质量的策略。