Novel Signaling Pathways Underlying Skeletal Muscle Atrophy

项目总结/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、某些药物治疗以及广泛的 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 关节炎和艾滋病肌肉萎缩的影响包括虚弱、活动受损、福尔斯、长时间 住院、延迟康复、丧失独立生活和死亡率增加。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， 因此代表了巨大的未满足的医疗需求。肌肉药物干预的发展 肌肉萎缩的分子基础是高度复杂的，不好理解的， 了解，但大部分尚未探索。这里提出的研究将有助于解决这一问题， 研究骨骼肌纤维中的应激诱导分子信号通路， 在至少3种临床重要情况下（老化， 固定和禁食）。我们最初是通过无偏见的基于系统的 迄今为止，这些战略已经确定了几个关键途径组成部分，包括Gadd 45 a（ 途径的核心），ATF 4（Gadd 45 a基因的重要上游调节因子）和MEKK 4（Gadd 45 a基因的重要上游调节因子）。 Gadd 45 a蛋白的重要下游介质）。我们建议的研究将建立在这些重要的基础上， 更深入地研究和理解控制Gadd 45 a的上游机制的初步发现 Gadd 45 a在肌肉中表达的病理生理学后果（Aim 2），以及Gadd 45 a在肌肉中表达的病理生理学后果（Aim 1）。 Gadd 45 a促进肌肉萎缩的下游机制（目的3）。这些研究应 显著推进我们对肌肉萎缩如何在分子水平上发生的理解， 实现几个长期目标，最重要的是开发新的治疗方法， 本发明提供了用于减轻患病、受伤和/或年老的人的肌肉无力和萎缩的方法。

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.