Accelerated and programmed mRNA decay by AU-rich binding protein AUF1 in the regulation of muscle regeneration

富含 AU 的结合蛋白 AUF1 在肌肉再生调节中加速和程序化 mRNA 降解

• 批准号: 10531231
• 负责人: Robert Schneider
• 金额: $ 46.54万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-12-11 至 2024-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10531231
• 关键词: AUF1A protein; Acceleration; Adult; Aging; Area; Binding Proteins; Cell Differentiation process; Cell Maintenance; Cell physiology; Development; Disease; Event; Gene Expression Regulation; Genes; Genetic Transcription; Maintenance; Mass Spectrum Analysis; Mediating; Messenger RNA; Molecular; Mus; Muscle; Muscle satellite cell; Myoblasts; Myopathy; Natural regeneration; Play; Proliferating; Proteins; Proteomics; Regulation; Research; Role; Skeletal Muscle; Testing; Therapeutic; Tissue Therapy; Transcriptional Activation; Transcriptional Regulation; Translating; effective therapy; genetic regulatory protein; interest; mRNA Decay; muscle regeneration; myogenesis; programs; protein protein interaction; regenerative tissue; satellite cell; stem cell division; stem cell fate; stem cells; tissue regeneration; tissue stem cells; transcription factor; wound

Project Summary There is currently significant interest in the potential for skeletal muscle stem cells, known as satellite cells, to be used in regenerative tissue therapy. The molecular understanding of skeletal muscle stem cell maintenance, fate determination and differentiation is crucial for translating research to the treatment of degenerative muscle diseases where there are few effective treatment options. This proposal investigates how the program of muscle stem cell maintenance, renewal and regeneration are orchestrated by selective, accelerated mRNA decay directed by the protein AUF1. This is a highly important but largely understudied area of gene regulation that plays a major role in programming and controlling adult tissue stem cell fate and tissue regeneration. We build on our previous studies and propose to identify the factors that regulate AUF1 expression in the satellite cell because AUF1 orchestrates the muscle regeneration program of the satellite cell, identify the satellite cell mRNAs selectively targeted for rapid degradation by AUF1 because this appears to stage the different developmental events of muscle regeneration, and how AUF1 orchestrates the progression of reprogramming by interacting with key regulatory proteins because this controls fate determination of satellite cells from activation to muscle regeneration.

项目摘要 目前，人们对骨骼肌干细胞（称为卫星细胞）的潜力非常感兴趣， 用于再生组织治疗。骨骼肌干细胞的分子生物学研究 维持、命运决定和分化对于将研究转化为治疗 退行性肌肉疾病，其中几乎没有有效的治疗选择。该提案探讨了如何 肌肉干细胞维持、更新和再生的程序是由选择性的， 加速由蛋白质AUF1指导的mRNA衰变。这是一个非常重要，但在很大程度上研究不足的问题。 在编程和控制成体组织干细胞命运中起主要作用的基因调控区域， 组织再生我们建立在我们以前的研究，并建议确定调节AUF1的因素， 因为AUF1协调卫星细胞的肌肉再生程序， 细胞，确定卫星细胞mRNA选择性靶向快速降解的AUF1，因为这似乎 来分期肌肉再生的不同发育事件，以及AUF1如何协调肌肉再生， 通过与关键调控蛋白相互作用进行重编程，因为这控制命运 从激活到肌肉再生的卫星细胞的测定。

项目成果

AUF1 gene transfer increases exercise performance and improves skeletal muscle deficit in adult mice.

• DOI: 10.1016/j.omtm.2021.07.005
• 发表时间: 2021-09-10
• 期刊: Molecular therapy. Methods & clinical development
• 作者: Abbadi D;Andrews JJ;Katsara O;Schneider RJ
• 通讯作者: Schneider RJ