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.

项目摘要 衰老是一个复杂的过程，其中多个分子途径的干扰有助于器官衰老。 恶化和与衰老有关的发病率和死亡率。老化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， 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。虽然取得了重大进展， 在理解随着衰老发生的转录变化时，很少有人知道后 转录事件（例如RNA修饰）控制衰老期间的蛋白质合成。在本提案中，我们 将使用肌肉老化来研究胃L3介导的m6 A mRNA甲基化在衰老背景下的作用 作为一个模型系统。我们假设胃L3依赖的mRNA甲基化调节了胃蛋白酶的表达过程。 通过控制特定的促肥大基因的翻译来延缓衰老。第一次，利用增益和 功能丧失的方法，我们将通过建立这种新的调控程序的分子特征， m6 A调节选择mRNA寿命的机制，并评估整体衰老-和胃L3- 依赖性翻译动力学（目的1），检查增强m6 A含量的治疗益处， 在临床相关动物模型中对抗肌肉减少症（目的2），并确定m6 A结合蛋白的作用 肌肉老化（目标3）。完成拟议的目标将允许发现一个新的机制 负责衰老的转录后调节，具有显著的治疗效果。