METTL3 in regulation of the aging process

METTL3 调节衰老过程

基本信息

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
项目类别：
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

项目摘要

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扰动有助于器官恶化和与衰老有关的发病率和死亡率。衰老过程的一个组成部分很严重基因表达的失调，导致老化细胞蛋白质组的变化，这可以妥协细胞功能。了解负责衰老诱导基因扰动的机制表达将是开发必要的医疗疗法的关键。尽管取得了重大进展在理解随着衰老发生的转录变化而进行的，几乎不知道如何转录事件，例如RNA修饰，控制衰老过程中的蛋白质合成。在这个建议中，我们将检查使用肌肉衰老的衰老中Mettl3介导的M6A mRNA甲基化的作用作为模型系统。我们假设Mettl3依赖性mRNA甲基化调节了通过控制特定促肌营养的mRNA的翻译来衰老。这是第一次利用增益和功能丧失方法我们将通过建立分子来表征这一新型调节程序 M6A调节精选mRNA寿命并评估全球衰老和METTL3-的机制依赖翻译动态（目标1），检查了增强M6A内容的治疗益处在临床相关的动物模型中抵消肌肉减少症（AIM 2），并定义M6A结合蛋白的作用在肌肉衰老中（目标3）。提出的目标的完成将允许揭露新的机制负责对衰老的转录后调节，并具有重大的治疗方法。