TAK1/TRAF6 Signaling in Skeletal Muscle

骨骼肌中的 TAK1/TRAF6 信号传导

基本信息

批准号：
8502172
负责人：
ASHOK KUMAR
金额：
$ 31.99万
依托单位：
UNIVERSITY OF LOUISVILLE
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-07-01 至 2016-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8502172
关键词：
Address Adult Affect Aging Apoptosis Area Atrophic Biochemical Biology Calcineurin Cell Culture Techniques Cell Cycle Arrest Cell Line Cell Surface Proteins Cells Child Chronic Chronic Disease Chronic Obstructive Airway Disease Complex Complication Cytoplasmic Tail Data Denervation Development Disease Drug Targeting Elements Embryonic Development Endocrine Event Family Fiber Genetic Growth Health Heart failure Human Impairment Inflammation Knockout Mice Laboratories Lead Link Lysine MAP Kinase Gene MAP3K7 gene MAPK14 gene Maintenance Malignant Neoplasms Mediating Methods Molecular Target Muscle Muscle Development Muscle Fibers Muscular Atrophy Myoblasts Myopathy Natural regeneration Neonatal Nude Mice Pathway interactions Perinatal Phenotype Phosphotransferases Physiological Play Polyubiquitin Process Protein Biosynthesis Proteins Regulation Rhabdomyosarcoma Role Sepsis Signal Transduction Signal Transduction Pathway Skeletal Muscle Staging Stem cells Stimulus Stress System TRAF6 gene Testing Transforming Growth Factors Travel Tumor Necrosis Factor Receptor Ubiquitination autocrine base human morbidity human mortality improved in vivo injured insight mouse model muscle form muscle regeneration myogenesis novel paracrine postnatal prevent protein degradation repaired response to injury sarcopenia satellite cell skeletal muscle growth skeletal muscle wasting transcription factor NF-AT c3 ubiquitin-protein ligase wasting

项目摘要

DESCRIPTION (provided by applicant): Skeletal muscle atrophy/wasting is a devastating complication of a wide range of diseases and conditions such as aging, disuse, chronic obstructive pulmonary disease, space travel, chronic heart failure, sepsis, and cancer. Myogenesis is the process that is required not only for the embryonic development of skeletal muscle but it is also an important element of certain types of postnatal growth and repair of injured myofibers. Impairment in myogenesis is the critical determinant of skeletal muscle-wasting in several chronic diseases and also development of rhabdomyosarcoma in children. Although significant progress has been made to understanding the processes of skeletal muscle formation and wasting, the upstream signaling events regulating skeletal muscle mass in various physiological and pathophysiological conditions remain poorly understood. We have accumulated strong evidence that supports a crucial role of TAK1/TRAF6 signaling complex in the acquisition and maintenance of skeletal muscle mass. Our preliminary studies have shown that both TRAF6 and TAK1 stimulate myogenic differentiation through novel Lysine-63-linked poly-ubiquitination mechanisms. TAK1 and TRAF6 are also required for MyoD-induced transformation of non-muscle cells into skeletal muscles. In adult skeletal muscle, the activation of TAK1/TRAF6 leads to inflammation, impairment in myofiber regeneration, and atrophy. To clearly establish the role and delineate the mechanisms of action of TAK1/TRAF6 complex in skeletal muscle, we will use genetic approaches including conditional knockout mice. Based on our preliminary data, we hypothesize that signaling through TAK1 and TRAF6 is required for the development of skeletal muscle but not for maintaining differentiated phenotype. Under stress conditions, the activation of TAK1 and TRAF6 stimulates catabolic pathways leading to skeletal muscle atrophy. To test this hypothesis, we propose to address the following three specific aims: 1) Investigate the signaling mechanisms by which TAK1 and TRAF6 regulate myogenic differentiation in cultured myoblasts; 2) Investigate the role and cellular mechanisms by which TAK1 and TRAF6 regulate skeletal muscle development in vivo; and 3) Delineate the mechanisms by which TAK1 and TRAF6 regulates regeneration and atrophy in adult skeletal muscles. Successful completion of this project will provide critical insights into the signaling mechanisms and establish TAK1 and TRAF6 as novel molecular targets to prevent skeletal muscle loss in various muscular disorders.

描述（由申请人提供）：骨骼肌萎缩/消耗是多种疾病和病症的破坏性并发症，例如衰老、废用、慢性阻塞性肺病、太空旅行、慢性心力衰竭、败血症和癌症。肌生成不仅是骨骼肌胚胎发育所需的过程，而且也是某些类型的出生后生长和受损肌纤维修复的重要组成部分。肌生成受损是多种慢性疾病中骨骼肌消耗以及儿童横纹肌肉瘤发展的关键决定因素。尽管在理解骨骼肌形成和消耗过程方面已经取得了重大进展，但在各种生理和病理生理条件下调节骨骼肌质量的上游信号事件仍然知之甚少。我们已经积累了强有力的证据，支持 TAK1/TRAF6 信号复合物在骨骼肌质量的获得和维持中的关键作用。我们的初步研究表明，TRAF6 和 TAK1 通过新型赖氨酸 63 连接的多聚泛素化机制刺激肌原性分化。 MyoD 诱导的非肌肉细胞向骨骼肌的转化也需要 TAK1 和 TRAF6。在成人骨骼肌中，TAK1/TRAF6 的激活会导致炎症、肌纤维再生受损和萎缩。为了清楚地确定 TAK1/TRAF6 复合物在骨骼肌中的作用并描述其作用机制，我们将使用包括条件敲除小鼠在内的遗传方法。根据我们的初步数据，我们假设通过 TAK1 和 TRAF6 的信号传导是骨骼肌发育所必需的，但不是维持分化表型所必需的。在应激条件下，TAK1 和 TRAF6 的激活会刺激分解代谢途径，导致骨骼肌萎缩。为了检验这一假设，我们建议解决以下三个具体目标：1）研究TAK1和TRAF6调节培养成肌细胞中肌源性分化的信号机制； 2）研究TAK1和TRAF6在体内调节骨骼肌发育的作用和细胞机制； 3) 描述 TAK1 和 TRAF6 调节成人骨骼肌再生和萎缩的机制。该项目的成功完成将为信号传导机制提供重要见解，并将 TAK1 和 TRAF6 确立为新的分子靶标，以防止各种肌肉疾病中的骨骼肌损失。