Mechanisms Underlying Muscle Development and Maintenance in Drosophila

项目总结 我们之前的工作重点是了解有助于开发 稳定成熟的肌腱连接(MTJ)。在上一个供资周期内取得的成果 确定了进化上保守的蛋白质不仅在形成过程中的重要作用，而且在 肌肉-肌腱相互作用的维持。有趣的是，MTJ的持续维护 形成与肌肉的动态平衡密切相关。下一次资助的总体目标 这一时期的目的是了解蛋白质平衡是如何在细胞内稳态的背景下进行调节的。这个 无法去除神经元或肌肉等未分裂细胞中的蛋白质聚集体是一个关键 神经退行性疾病和肌病的发生和发展中的因素 是衰老细胞的细胞标志。虽然蛋白质聚集性疾病有共同的特征，但它 普遍认为导致蛋白质聚集的分子途径不可能是 用一个单一的机制来解释。在导致肌病的蛋白质聚集性疾病中， 总的趋势是聚集的蛋白质和细胞器在区域内积累 没有肌肉组织。然而，启动Z盘的细胞和机械触发器 肌纤维的解体和移位尚不清楚。在这里，我们使用保守性的突变 以果蝇基因为切入点，揭示导致 以肌肉为模型细胞类型的蛋白质聚集和最终的细胞退化。 总体而言，我们预计将发现以下未被认可的方面，包括但不限于： 有助于蛋白稳定的新成分；确定肌酶活性的靶点；以及 确定自噬如何在清除蛋白质聚集体中发挥作用。一个强大的 基因分析、生物化学、细胞生物学和实时成像方法的结合将 回答这些问题。我们希望这个项目将从根本上推进我们的 了解蛋白质降解是如何被调节以防止细胞退化和 提供有关蛋白质聚集体如何被有效清除以减少疾病的新见解 各州。

PROJECT SUMMARY Our prior work focused on understanding mechanisms that contribute to the development of a stable, mature myotendinous junction (MTJ). Results obtained during the past funding cycle identified essential roles for evolutionarily conserved proteins not just in the formation, but also in the maintenance, of muscle-tendon interactions. Interestingly, continued maintenance of MTJ formation is intimately linked to muscle homeostasis. The overall goal during the next funding period is to understand how proteostasis is regulated in the context of cell homeostasis. The inability to remove protein aggregates in non-dividing cells such as neurons or muscles is a key factor in the development and progression of neurodegenerative diseases and myopathies and is a cellular hallmark of aging cells. While protein aggregate diseases share common features, it is widely assumed that the molecular pathways that lead to protein aggregation cannot be explained by a single mechanism. In protein aggregation disease that cause myopathies, a general trend has emerged in which aggregated proteins and organelles accumulate in regions devoid of muscle tissue. However, the cellular and mechanical triggers that initiate Z-disk disintegration and myofiber displacement are unclear. Here we employ mutations in conserved Drosophila genes as an entry point to uncover cellular and molecular mechanisms that lead to protein aggregation and ultimately cellular degeneration using muscle as a model cell type. Overall, we expect to uncover unrecognized aspects of, including, but not limited to: uncovering novel components that contribute to proteostasis; identifying muscle targets of kinase activity; and determining how autophagy cooperates in the clearance of protein aggregates. A powerful combination of genetic analysis, biochemistry, cell biology, and live imaging approaches will address these questions. We expect that this project will fundamentally advance our understanding of how protein degradation is regulated to prevent cellular degeneration and to provide fresh insights into how protein aggregates can be effectively cleared to reduce disease states.