MYD88 Signaling in Mammalian Myoblast Fusion

哺乳动物成肌细胞融合中的 MYD88 信号转导

基本信息

批准号：
9336240
负责人：
ASHOK KUMAR
金额：
$ 33.74万
依托单位：
UNIVERSITY OF LOUISVILLE
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-09-14 至 2020-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9336240
关键词：
3&apos Untranslated Regions Ablation Adaptor Signaling Protein Address Adult Age Attenuated Binding Bioinformatics Caliber Cell fusion Cells Consensus DNA Sequence Defect Development Drosophila genus Drosophila melanogaster Embryonic Development Event Family Gene Expression Genes Genetic Genetic Transcription Goals Growth Hypertrophy Impairment In Vitro Injury Innate Immune Response Interleukin-1 Knock-out Knockout Mice Knowledge MAP Kinase Gene Mediating MicroRNAs Molecular Molecular and Cellular Biology Mus Muscle Muscle Cells Muscle Development Muscle Fibers Muscular Atrophy MyD88 protein Myelogenous MyoD Protein Myoblasts Myogenic Regulatory Factors Myogenin Myopathy Natural regeneration Neonatal Pathway interactions Pattern Play Process Promoter Regions Recruitment Activity Research Role Seminal Signal Pathway Signal Transduction Skeletal Development Skeletal Muscle Small Interfering RNA System TLR3 gene Testing Therapeutic Toll-like receptors Transcript Vertebrates WNT Signaling Pathway Wild Type Mouse base experimental study improved in vivo insight interleukin-18 receptor knock-down mouse model muscle form muscle hypertrophy myogenesis new therapeutic target novel therapeutics overexpression promoter public health relevance receptor repaired response response to injury skeletal muscle growth

项目摘要

DESCRIPTION (provided by PI): Myoblast fusion is a critical event that is required not only for the development of skeletal muscle during embryogenesis but also for the regeneration of adult myofibers upon injury and for load-induced skeletal muscle hypertrophy. Augmenting the natural process of muscle cell fusion in existing or introduced myogenic cells has enormous therapeutic potential to treat degenerative muscle diseases. However, the mechanisms of myoblast fusion in vertebrates remain less understood. Accumulating evidence suggests that myoblast fusion in mammalian system involves the activation of specific cell signaling pathways such as MAPK, non-canonical NF-κB, canonical Wnt signaling. However, the upstream signaling mechanisms leading to their activation and how the activation of these pathways promotes myoblast fusion during myogenesis remain poorly understood. Our preliminary studies have identified that myeloid differentiation primary response gene 88 (Myd88) is a critical regulator of myoblast fusion both in vitro and in vivo. Our results show that the levels of Myd88 are increased during myogenesis. Genetic ablation of Myd88 impairs myoblast fusion whereas overexpression of Myd88 enhances the formation of myotubes in cultured myoblasts. Furthermore, we have obtained initial evidence that Myd88 regulates the activation of specific profusion signaling pathways during myogenesis. Based on our preliminary studies, we have proposed to establish the role and delineate the signaling and molecular mechanisms by which Myd88 mediates skeletal muscle formation in vitro and in vivo. Our working hypotheses are: (I) Myd88 promotes myoblast fusion in multiple conditions through augmenting the gene expression of specific profusion molecules; (II) Myd88 coordinates the activation of canonical Wnt and non-canonical NF-κB signaling to promote myoblast fusion during myogenesis; (III) Both transcriptional and post-transcriptional mechanisms regulate the levels of Myd88 in differentiating myoblasts. We will test these hypotheses by addressing the following three specific aims. Aim I: Establish the role and investigate molecular mechanisms by which Myd88 mediates myoblast fusion; Aim II: Investigate the signaling networks through which Myd88 promotes myoblast fusion; and Aim III: Investigate the mechanisms by which levels of Myd88 are increased during myogenesis. Successful completion of this project will provide critical insights into the mechanisms of myoblast fusion and will lead to the identification of novel drug targets for treatment of muscle disorders.

描述（由PI提供）：成肌细胞融合是一个关键事件，不仅需要在胚胎发生过程中发展骨骼肌，而且还需要成年肌纤维在受伤和负荷诱导的骨骼肌肥大时的再生。在现有或引入的肌原细胞中增加肌肉细胞融合的自然过程具有治疗退化性肌肉疾病的巨大治疗潜力。但是，脊椎动物中肌细胞融合的机制仍然不太了解。积累的证据表明，哺乳动物系统中的肌细胞融合涉及特定细胞信号通路，例如MAPK，非典型的NF-κB，规范WNT信号传导。然而，上游信号传导机制导致它们激活，以及这些途径的激活如何促进成肌作用过程中的成肌细胞融合。我们的初步研究表明，髓样分化的主要反应基因88（MYD88）是体外和体内肌细胞融合的关键调节剂。我们的结果表明，在肌发生过程中，MyD88的水平升高。 MyD88的遗传消融会损害成肌细胞融合，而MyD88的过表达增强了培养的肌细胞中肌管的形成。此外，我们获得了最初的证据，表明MYD88调节在肌发生过程中的特定大量信号传导途径的激活。基于我们的初步研究，我们提出了建立角色并描述MyD88在体外和体内介导骨骼肌形成的信号传导和分子机制。我们的工作假设是：（i）MyD88通过增强特定大量分子的基因表达来促进多种条件下的肌细胞融合；（ii）MyD88协调规范Wnt和非典型的NF-κB信号的激活，以促进肌生成过程中的成肌细胞融合；（iii）转录和转录后机制在区分成肌细胞中调节MyD88的水平。我们将通过解决以下三个特定目标来检验这些假设。目的I：确定角色并研究MyD88介导肌细胞融合的分子机制； AIM II：研究MyD88促进肌细胞融合的信号网络； AIM III：研究在肌发生过程中MyD88水平升高的机制。该项目的成功完成将为肌细胞融合的机制提供关键的见解，并将导致鉴定出新的药物靶标的治疗肌肉疾病。