Novel signaling pathways underlying skeletal muscle atrophy

骨骼肌萎缩的新信号通路

• 批准号: 9922199
• 负责人: Christopher M Adams
• 金额: $ 52.35万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-30 至 2021-02-12
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9922199
• 关键词: AIDS/HIV problem; Achievement; Address; Affect; Aging; Atrophic; Binding; Biochemical; Biology; Cell physiology; Chronic Disease; Chronic Obstructive Airway Disease; Cirrhosis; Clinical; Complex; Critical Illness; Critical Pathways; Data; Development; Diabetes Mellitus; Fasting; GADD45A gene; Gene Expression; Genetic Transcription; Goals; Health; Heart failure; Hospitalization; Immobilization; Impairment; Independent Living; Intervention; Kidney Failure; Knockout Mice; Lead; MAP Kinase Kinase Kinase; Malignant Neoplasms; Malnutrition; Mediating; Mediator of activation protein; Medical; Mitogen-Activated Protein Kinase Kinases; Molecular; Muscle; Muscle Fibers; Muscle Proteins; Muscle Weakness; Muscle function; Muscular Atrophy; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacological Treatment; Pharmacology; Phenotype; Phosphorylation; Prevalence; Protein Kinase; Protein Tyrosine Phosphatase; Protein phosphatase; Proteins; Proteome; Proteomics; Quality of life; RNA Interference; Rehabilitation therapy; Research; Rheumatoid Arthritis; Role; Severities; Signal Pathway; Signaling Protein; Skeletal Muscle; Stress; System; Testing; Work; aged; base; falls; genome-wide; globular protein; in vivo; injured; knock-down; mortality; mouse model; muscle form; novel; novel therapeutic intervention; overexpression; programs; skeletal muscle wasting; therapeutic target; transcription factor

PROJECT SUMMARY / ABSTRACT Skeletal muscle atrophy diminishes the health and quality of life of tens of millions of people. Causes of muscle atrophy include aging, muscle disuse, malnutrition, critical illness, certain medications, and a wide range of chronic illnesses including cancer, heart failure, COPD, diabetes, renal failure, cirrhosis, rheumatoid arthritis, and HIV/AIDS. Effects of muscle atrophy include weakness, impaired activity, falls, prolonged hospitalization, delayed rehabilitation, loss of independent living, and increased mortality. Importantly, despite its prevalence and severity, skeletal muscle atrophy lacks a specific and effective pharmacologic therapy and thus represents an enormous unmet medical need. Development of pharmacologic interventions for muscle atrophy has been hindered by the fact that the molecular basis of muscle atrophy is highly complex, poorly understood, and still largely unexplored. The research proposed here would help to address this issue by investigating a stress-inducible molecular signaling pathway in skeletal muscle fibers that appears to be necessary and sufficient for muscle atrophy during at least 3 clinically important scenarios (aging, immobilization and fasting). We originally discovered this pathway through unbiased systems-based strategies, which have, to date, identified several critical pathway components, including Gadd45a (the pathway's centerpiece), ATF4 (an essential upstream regulator of the Gadd45a gene), and MEKK4 (an important downstream mediator of the Gadd45a protein). Our proposed studies will build upon these important initial findings to more deeply investigate and understand the upstream mechanisms that control Gadd45a expression (Aim 1), the pathophysiological consequences of Gadd45a expression in muscle (Aim 2), and the downstream mechanism(s) by which Gadd45a promotes muscle atrophy (Aim 3). These studies should significantly advance our understanding of how muscle atrophy occurs at the molecular level and facilitate achievement of several longer-term goals, the most important being the development of new therapeutic approaches for reducing muscle weakness and atrophy in people who are ill, injured and/or aged.

项目概要/摘要 骨骼肌萎缩降低了数千万人的健康和生活质量。原因 肌肉萎缩包括衰老、肌肉废用、营养不良、危重疾病、某些药物和广泛的疾病 一系列慢性疾病，包括癌症、心力衰竭、慢性阻塞性肺病、糖尿病、肾衰竭、肝硬化、类风湿 关节炎和艾滋病毒/艾滋病。肌肉萎缩的影响包括无力、活动受损、跌倒、长时间 住院、康复延迟、丧失独立生活以及死亡率增加。重要的是，尽管 由于其患病率和严重程度，骨骼肌萎缩缺乏特异性和有效的药物治疗方法， 因此，存在巨大的未满足的医疗需求。肌肉药物干预措施的开发 肌肉萎缩的分子基础非常复杂，而且很难理解，这一事实阻碍了萎缩的发展。 已被理解，但在很大程度上仍未被探索。这里提出的研究将有助于解决这个问题 研究骨骼肌纤维中应激诱导的分子信号传导途径，该途径似乎是 在至少 3 种临床重要情况（衰老、 固定和禁食）。我们最初通过基于系统的公正发现了这条途径 迄今为止，该策略已确定了几个关键的通路成分，包括 Gadd45a（ 途径的核心）、ATF4（Gadd45a 基因的重要上游调节因子）和 MEKK4（ Gadd45a 蛋白的重要下游介质）。我们提出的研究将建立在这些重要的基础上 初步发现可更深入地研究和了解控制 Gadd45a 的上游机制 表达（目标 1）、肌肉中 Gadd45a 表达的病理生理学后果（目标 2）以及 Gadd45a 促进肌肉萎缩的下游机制（目标 3）。这些研究应该 显着增进我们对分子水平上肌肉萎缩如何发生的理解，并促进 实现几个长期目标，最重要的是开发新的治疗方法 减少生病、受伤和/或老年人肌肉无力和萎缩的方法。