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：
9144184
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/9144184
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 Goals Growth Health Hypertrophy Immune response Impairment In Vitro Injury Interleukin-1 Knock-out Knockout Mice Knowledge Lead MAP Kinase Gene Mediating MicroRNAs Molecular Molecular and Cellular Biology Mus Muscle Muscle Cells Muscle Fibers Muscular Atrophy MyD88 protein Myelogenous Myoblasts Myogenic Regulatory Factors Myogenin Myopathy Natural regeneration Neonatal Pathway interactions Pattern Play Process Promoter Regions Research Role Seminal Signal Pathway Signal Transduction Skeletal Muscle Small Interfering RNA System TLR3 gene Testing Therapeutic Toll-like receptors Transcript Vertebrates Wild Type Mouse Work base improved in vivo insight interleukin-18 receptor knock-down mouse model muscle form muscle hypertrophy myogenesis new therapeutic target novel therapeutics overexpression promoter receptor repaired research study 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，不仅是胚胎发生过程中骨骼肌发育所必需的，而且也是受伤后成体肌纤维的再生和负荷诱导的骨骼肥大所必需的，以增强肌肉的自然过程。现有或引入的生肌细胞中的细胞融合对于治疗退行性肌肉疾病具有巨大的治疗潜力，然而，脊椎动物中成肌细胞融合的机制仍知之甚少。越来越多的证据表明，哺乳动物系统中的成肌细胞融合涉及特定细胞信号通路的激活，例如MAPK、非经典NF-κB、经典Wnt信号传导，然而，导致它们激活的上游信号传导机制以及这些通路的激活如何促进。我们的初步研究表明，骨髓分化初级反应基因 88 (Myd88) 是体外和体内成肌细胞融合的关键调节因子。结果表明，Myd88 的水平在肌生成过程中增加，Myd88 的基因消除会损害成肌细胞融合，而 Myd88 的过度表达会增强培养的成肌细胞中肌管的形成。基于我们的初步研究，我们建议确定 Myd88 介导的作用并描述其信号传导和分子机制。我们的工作假设是：（I）Myd88 通过增强特定丰富分子的基因表达来促进成肌细胞融合；（II）Myd88 协调经典 Wnt 和非经典 NF- 的激活。 κB信号在肌生成过程中促进成肌细胞融合；（III）转录和转录后机制在分化成肌细胞中调节Myd88的水平。通过解决以下三个具体目标来检验这些假设：建立 Myd88 介导成肌细胞融合的分子机制；目标 II：研究 Myd88 促进成肌细胞融合的信号网络；目标 III：研究 Myd88 促进成肌细胞融合的机制； Myd88 的水平在肌生成过程中增加，该项目的成功完成将为成肌细胞融合机制提供重要的见解，并将导致识别肌肉治疗的新药物靶点。失调。