Muscle Protein Complex Assembly and Maintenance

横纹肌的可收缩肌节是最复杂的细胞蛋白组合之一，我们对其主要成分进行了数十年的研究。相比之下，在任何系统中，肌节组装的精确步骤，以及在活动期间维持它们的稳态过程，在细胞或分子水平上都知之甚少。我们知道肌肉的组成，但很少知道它们是如何组装的，或在损伤后拆卸。质量控制（QC）调节蛋白质折叠和稳态，以及蛋白质在时间和空间上的分阶段组装是至关重要的。我们的计划是了解组装和维持肌节的分子途径，或在损伤后允许修复或再生。本提案的重点将放在调节肌节成分合成的转录控制网络，粗丝组装的转录后QC调控，以及在正常发育过程中两者之间的协调，以及当肌节结构被遗传病变扰乱时。目标是：

The contractile sarcomere of striated muscle is one of the most complex cellular protein assemblies, and we have studied the major components for decades. In contrast, the precise steps in the assembly of sarcomeres, as well as the homeostatic processes that maintain them during activity are poorly understood at the cellular or molecular level in any system. We know the components of muscle, but little about how they are assembled, or disassembled following damage. Quality control (QC) regulation of protein folding and homeostasis, as well as staged assembly of proteins in time and space, is critically important. Our program is to understand the molecular pathways that assemble and maintain the sarcomere, or allow repair or regeneration after damage. The focus of this proposal will be on the transcriptional control networks that regulate synthesis of sarcomere components, the posttranscriptional QC regulation of thick filament assembly, and the coordination between the two during normal development, as well as when the structure of the sarcomere is perturbed by genetic lesion. The aims are: