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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.

项目总结