Mechanisms Underlying Muscle Development and Maintenance in Drosophila

项目摘要 我们之前的工作集中在理解有助于发展的机制， 稳定、成熟的肌腱连接（MTJ）。上一个供资周期取得的成果 确定了进化上保守的蛋白质的重要作用，不仅在形成中，而且在 肌肉-肌腱相互作用的维持。有趣的是，持续维护MTJ 它的形成与肌肉内稳态密切相关。下一轮融资的总体目标 这一时期的重点是了解蛋白质稳态是如何在细胞内稳态的背景下进行调节的。的 不能去除非分裂细胞如神经元或肌肉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展和进展的因素， 是衰老细胞的细胞标志虽然蛋白质聚集疾病有共同的特点， 人们普遍认为，导致蛋白质聚集的分子途径不能被 用一种机制来解释。在引起肌病的蛋白质聚集疾病中， 总的趋势是聚集的蛋白质和细胞器聚集在区域中 没有肌肉组织然而，启动Z盘的细胞和机械触发器 崩解和肌纤维移位尚不清楚。在这里，我们采用保守的突变， 果蝇基因作为一个切入点，揭示细胞和分子机制，导致 蛋白质聚集和最终的细胞变性，使用肌肉作为模型细胞类型。 总的来说，我们希望发现未被认识到的方面，包括但不限于： 有助于蛋白质稳态的新组分;鉴定激酶活性的肌肉靶点;以及 确定自噬如何在蛋白质聚集体的清除中合作。一个强大 遗传分析、生物化学、细胞生物学和活体成像方法的组合将 来解决这些问题。我们希望，该项目将从根本上推动我们的 了解蛋白质降解是如何调节的，以防止细胞退化， 为如何有效清除蛋白质聚集体以减少疾病提供了新的见解 states.

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.