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/浪费是多种疾病和疾病的毁灭性并发症，例如衰老，废药，慢性阻塞性肺部疾病，太空旅行，慢性心力衰竭，败血症和癌症。肌发生不仅是骨骼肌的胚胎发育所必需的过程，而且它也是某些类型的产后生长和受伤肌纤维修复的重要元素。肌发生的损害是几种慢性疾病中骨骼肌浪费的关键决定因素，也是儿童横纹肌肉瘤的发展。尽管在理解骨骼肌形成和浪费的过程中取得了重大进展，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。我们积累了有力的证据，该证据支持TAK1/TRAF6信号传导复合物在骨骼肌质量的获取和维持中的关键作用。我们的初步研究表明，TRAF6和TAK1均通过新型赖氨酸-63连接的多泛素化机制刺激肌源分化。 TAK1和TRAF6也需要Myod诱导的非肌肉细胞转化为骨骼肌。在成年骨骼肌中，tak1/traf6的激活导致炎症，肌纤维再生障碍和萎缩。为了清楚地确定骨骼肌中TAK1/TRAF6复合物的作用机理，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展所必需的，而不是维持分化的表型。在压力条件下，TAK1和TRAF6的激活刺激了导致骨骼肌萎缩的分解代谢途径。为了检验这一假设，我们建议解决以下三个特定目的：1）研究TAK1和TRAF6调节培养的肌细胞中肌源性分化的信号传导机制； 2）研究TAK1和TRAF6调节体内骨骼肌发育的作用和细胞机制； 3）描述TAK1和TRAF6调节成人骨骼肌的再生和萎缩的机制。该项目的成功完成将提供对信号机制的关键见解，并将TAK1和TRAF6作为新的分子靶标建立，以防止各种肌肉疾病中的骨骼肌损失。