METTL3 in regulation of the aging process

METTL3 调节衰老过程

• 批准号: 10748833
• 负责人: Federica Accornero
• 金额: --
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-01 至 2023-08-02
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10748833
• 关键词: Address; Adopted; Affect; Aging; Animal Model; Atrophic; Binding; Binding Proteins; Biological; Biological Models; Cell physiology; Complex; Data; Dependovirus; Deterioration; Engineering; Enzymes; Equilibrium; Event; Exercise Tolerance; Functional disorder; Gene Expression; Gene Expression Process; Genes; Genetic; Genetic Transcription; Growth; Health; Homeostasis; Hypertrophy; Knockout Mice; Life; Maintenance; Mediating; Mediator; Messenger RNA; Metabolic; Methylation; Methyltransferase; Modeling; Modification; Molecular; Morbidity - disease rate; Movement; Mus; Muscle; Muscle function; Muscular Atrophy; Organ; Pathologic; Pathway interactions; Phenotype; Post-Transcriptional Regulation; Process; Protein Biosynthesis; Proteome; Quality of life; RNA; RNA methylation; RNA-Binding Proteins; Regulation; Ribosomes; Role; Signal Transduction; Skeletal Muscle; Stimulus; Testing; Therapeutic; Time; Transcriptional Regulation; Translating; Translations; Tropism; aged; cell age; clinically relevant; experimental study; gain of function; healthy aging; in vivo; insight; loss of function; mRNA Translation; medically necessary care; mortality; mouse model; muscle aging; muscle form; novel; novel strategies; overexpression; posttranscriptional; preservation; prevent; programs; prospective; protein degradation; receptor expression; sarcopenia; tool; wasting

PROJECT SUMMARY Aging is a complex process where perturbation of multiple molecular pathways contributes to organ deterioration and aging-related morbidity and mortality. One component of the aging process is severe dysregulation of gene expression that contributes to changes in the proteome of aged cells, which can compromise cell function. Understanding the mechanisms responsible for aging-induced perturbation of gene expression will be key to develop the necessary medical therapies. Although significant progress has been made in understanding the transcriptional changes occurring with aging, very little is known about how post- transcriptional events, such as RNA modifications, control protein synthesis during aging. In this proposal we will examine the role of METTL3-mediated m6A mRNA methylation in the context of aging using muscle aging as a model system. We hypothesize that METTL3-dependent mRNA methylation regulates the process of aging by controlling the translation of specific pro-hypertrophic mRNAs. For the first time, utilizing gain- and loss-of-function approaches we will characterize this novel regulatory program by establishing the molecular mechanisms by which m6A regulates the life of select mRNAs and assess the global aging- and METTL3- dependent translation dynamics (aim 1), examining the therapeutic benefit of enhancing m6A content to counteract sarcopenia in clinically relevant animal models (aim 2), and define the role of m6A binding proteins in muscle aging (aim 3). Completion of the proposed aims will allow the uncovering of a novel mechanism responsible for post-transcriptional regulation of aging with significant therapeutics ramifications.

项目概要 衰老是一个复杂的过程，多个分子途径的扰动会导致器官 恶化以及与衰老相关的发病率和死亡率。衰老过程的一个组成部分是严重的 基因表达失调导致衰老细胞蛋白质组的变化，这可以 损害细胞功能。了解衰老引起的基因扰动的机制 表达将是开发必要的医学疗法的关键。尽管已经取得了重大进展 在了解衰老过程中发生的转录变化时，人们对衰老后如何发生的情况知之甚少。 RNA修饰等转录事件控制衰老过程中的蛋白质合成。在这个提案中我们 将利用肌肉老化研究 METTL3 介导的 m6A mRNA 甲基化在衰老背景下的作用 作为模型系统。我们假设 METTL3 依赖性 mRNA 甲基化调节这一过程 通过控制特定促肥大 mRNA 的翻译来实现衰老。第一次，利用增益和 功能丧失方法我们​​将通过建立分子 m6A 调节特定 mRNA 寿命并评估整体衰老和 METTL3 的机制 依赖翻译动力学（目标 1），检查增强 m6A 含量的治疗益处 在临床相关动物模型中对抗肌肉减少症（目标 2），并定义 m6A 结合蛋白的作用 肌肉老化（目标 3）。完成拟议的目标将揭示一种新的机制 负责衰老的转录后调节，具有显着的治疗影响。