MicroRNA Modulation of Aging & Healthspan

MicroRNA 调节衰老

• 批准号: 8017580
• 负责人: MONICA A. DRISCOLL
• 金额: $ 31.24万
• 依托单位: RUTGERS, THE STATE UNIV OF N.J.
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-01 至 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8017580
• 关键词: Address; Adopted; Adult; Age; Aging; Aging-Related Process; Alleles; Am 80; Animal Feed; Animals; Biological; Biological Assay; Biological Models; Biology; Biology of Aging; Brain; Caenorhabditis elegans; Cells; Collection; Data; Disease; Dissection; Family member; Food; Foundations; Functional RNA; Future; Genes; Genetic; Genetic Models; Genomics; Goals; Health; Homologous Gene; Human; Incidence; Intervention; Life; Lipofuscin; Longevity; Longevity Pathway; Messenger RNA; Metabolism; MicroRNAs; Mission; Modeling; Molecular; Molecular Genetics; Myocardium; National Institute on Aging; Nematoda; Organism; Outcome; Pathway interactions; Pattern; Phenotype; Physiological; Pigments; Play; Process; Pump; Reagent; Regimen; Regulation; Regulator Genes; Repression; Research; Role; Skeletal Muscle; Specificity; Stress; Structure; Synaptic plasticity; Temperature; Testing; Therapeutic; Tissues; Transcript; Tumor Suppressor Proteins; Work; age related; combat; design; dietary restriction; functional decline; healthy aging; improved; in vivo; insight; interest; middle age; mutant; novel; pharynx muscle; public health relevance; research study; sarcopenia; small molecule; therapy design

DESCRIPTION (provided by applicant): A key challenge of current aging research is to identify strategies for healthy aging in which mid-life vigor is prolonged. We use the powerful genetic model system C. elegans to decipher how genes influence healthspan and to identify molecular ways to combat the general functional decline that accompanies aging. microRNAs (miRNAs) are small molecules that target partially homologous mRNA transcripts to down-regulate their expression via a prevalent and conserved gene regulatory mechanism. miRNA roles in aging are just beginning to be addressed, but initial work indicates that expression of many C. elegans miRNAs changes during adult life (in fact there is a major mid-life decline "crisis" in miRNA levels in this animal) and that many miRNAs may impact the quality of aging, or healthspan. Characterizing this major biological component of middle-age decline will be critical for the overall effort of understanding how gene networks interact to influence aging quality. We therefore propose to test how extensively the conserved microRNAs of this one animal influence healthspan at the tissue and organism levels. We will also study in detail the mechanisms by which two miRNAs with mammalian homologs involved in processes relevant to problems in human aging modulate nematode healthspan. A goal is to document some of the first examples in which manipulation of miRNA expression in vivo might be exploited to extend healthspan. We propose two aims: Aim1: To establish a genomic overview of how the conserved miRNAs of C. elegans impact the biology of aging. We will characterize aging phenotypes of C. elegans mutants of mir genes that are conserved between nematodes and humans, studying locomotory decline, rate of lipofuscin accumulation, pharyngeal muscle pumping rate, and thermotolerance. Data will provide an overview of how conserved miRNAs impact healthspan and may identify key "node" miRNA modulators of the process. Aim 2: To probe mechanisms by which two miRNAs that are differentially regulated in middle-age alter healthspan, and to model miRNA interventions that increase the quality of aging. We will focus on mechanistic dissection of healthspan-promoting miRNA mir-34, which increases in concentration in middle age, and healthspan-promoting mir-45, which decreases in middle age. The mammalian counterpart of mir-34 is documented to have tumor suppressor activity; the mammalian counterpart of mir-45 influences formation of structures implicated in brain synaptic plasticity. Our studies will include detailed phenotypic analyses of healthspan phenotypes, modulation of expression of specific miRNAs in whole-animal context to alter healthspan outcomes, and specific tests of working models for bioactivity in aging. Overall, the studies we propose address a major gap in our understanding of the genes that impact aging. Our findings might be extrapolated to influence experiments in higher organisms that may ultimately inspire design of healthspan-extending interventions. PUBLIC HEALTH RELEVANCE: Our interest is in genes that promote healthy and robust aging, a topic central to the mission of the National Institute on Aging. Our work, and that of others, has implicated microRNAs--small non-coding RNAs that down-regulate expression of target mRNA transcripts--in the aging process. We have found that ~ half of C. elegans miRNAs change in abundance over adult life, with most lowering in concentration in middle age. Because miRNAs are proposed to play an important role in biological robustness (which diminishes with age), we speculate that miRNAs as a general class will have a large impact on healthy aging. As we screen miRNA mutants for their influence on aging biology and characterize specific mechanisms of miRNA action, we will show how these small molecule regulators might be used to extend the period of healthy aging in a physiological setting. Indeed, at least one miRNA on which we will focus mechanistic studies appears to regulate dietary restriction metabolism-a conserved healthy state characterized by increased vigor, decreased incidence of age-associated disease, and extended lifespan. Our findings may ultimately inspire design of healthspan-extending interventions in humans.

描述（由申请人提供）：当前衰老研究的一个主要挑战是确定延长中年活力的健康衰老策略。我们使用强大的遗传模型系统C.秀丽隐杆线虫来破译基因如何影响健康范围，并确定分子方式来应对伴随衰老的一般功能下降。 microRNA（miRNA）是小分子，它们靶向部分同源mRNA转录本，通过普遍和保守的基因调节机制下调其表达。 miRNA在衰老中的作用才刚刚开始解决，但是最初的工作表明，许多秀丽隐杆线虫在成人生活中的表达变化（实际上，这种动物中miRNA水平的中年危机大幅下降），并且许多miRNA可能会影响衰老的质量或健康范围。表征中年下降的这一主要生物学成分对于理解基因网络如何相互作用以影响衰老质量的整体努力至关重要。因此，我们建议测试该动物在组织和生物体水平上的保守微区。我们还将详细研究两种与人类衰老问题调节线虫HealthSpan相关的哺乳动物同源物的miRNA与哺乳动物同源物有关的机制。一个目标是记录一些第一个例子，其中可能利用对体内miRNA表达的操纵以扩展健康范围。我们提出了两个目标：AIM1：建立基因组概述，了解秀丽隐杆线虫的保守miRNA如何影响衰老的生物学。我们将表征线虫和人类之间保守的miR基因的秀丽隐杆线虫突变体的衰老表型，研究运动下降，脂肪霉素的积累速率，咽肌抽水速率和热耐剂。数据将概述保守的miRNA影响健康范围，并可以识别该过程的关键“节点” miRNA调节剂。目的2：探测在中年龄较大的健康范围内受到差异调节的两个miRNA的探测机制，并模拟增加衰老质量的miRNA干预措施。我们将重点关注促进HealthSpan的miRNA miR-34的机械解剖，该miRNA miR-34在中年的浓度增加，以及促进健康范围的miR-45，这会减少中年。记录了miR-34的哺乳动物对应物具有肿瘤抑制活性。 miR-45的哺乳动物对应物影响与脑突触可塑性有关的结构的形成。我们的研究将包括对HealthSpan表型的详细表型分析，在整个动物环境中调节特定miRNA以改变健康状态结果的表达以及对衰老生物活性的工作模型的特定测试。总体而言，我们提出的研究解决了对影响衰老的基因的理解的主要差距。我们的发现可能会推断出来，以影响较高生物体的实验，这些实验可能最终激发了对健康范围的干预措施的设计。 公共卫生相关性：我们的兴趣在于促进健康，健壮的衰老的基因，这是美国国家衰老研究所任务的核心。在衰老过程中，我们的工作以及其他的工作暗示了microRNAS-微小的非编码RNA，这些非编码RNA下调了目标mRNA转录本的表达。我们发现，在成年人生活中，秀丽隐杆线虫中有一半的miRNA变化，大多数在中年的浓度下降。由于提议miRNA在生物鲁棒性中发挥重要作用（随着年龄的增长而减少），因此我们推测，作为一般阶级的miRNA将对健康衰老产生很大的影响。当我们筛选miRNA突变体对衰老生物学的影响并表征miRNA作用的特定机制时，我们将展示如何使用这些小分子调节剂在生理环境中延长健康衰老的时期。实际上，至少有一个miRNA我们将重点研究机理研究似乎调节饮食限制代谢 - 保守的健康状态，其特征是活力增加，与年龄相关疾病的发病率降低和寿命延长。我们的发现最终可能会激发人们对人类延伸干预措施的设计。