Mechanisms Underlying Muscle Development and Maintenance in Drosophila

果蝇肌肉发育和维持的机制

基本信息

批准号：
9886915
负责人：
Erika Rae Geisbrecht
金额：
$ 34.3万
依托单位：
KANSAS STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-08-01 至 2025-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/9886915
关键词：
Address Affect Autophagocytosis BAG3 gene Biochemical Biochemical Pathway Biochemistry Biological Biological Process Biopsy Carrier Proteins Cell Aging Cell model Cell physiology Cells Cellular biology Cessation of life Characteristics Client Complex Data Development Disease Drosophila genus Event F-Actin Funding Genes Genetic Structures Goals Homeostasis Human Interphase Cell Label Lead Link Maintenance Mechanics Mediating Microtubules Modeling Molecular Muscle Muscle Cells Muscle Development Mutation Myopathy Neurodegenerative Disorders Neurons Organelles Pathway interactions Patients Phosphorylation Phosphotransferases Prevention Protein Region Protein-Serine-Threonine Kinases Proteins Regulation Role Sagittaria Sarcomeres Signal Pathway Site Structure System Tendon structure Testing Therapeutic Ubiquitin Work cell type experimental study filamin genetic analysis imaging approach in vivo insight mutant novel overexpression prevent protein aggregation protein degradation proteostasis recruit tissue degeneration trend

项目摘要

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.

项目摘要我们先前的工作着重于理解有助于发展的机制稳定，成熟的肌无力连接点（MTJ）。在过去的资金周期中获得的结果确定了进化保守蛋白的基本作用，不仅在形成中，而且在维护肌肉 - 肌肉相互作用。有趣的是，继续维护MTJ 形成与肌肉稳态密切相关。下一次资金的总体目标时期是了解如何在细胞稳态的背景下调节蛋白质的。这无法去除非分散细胞（例如神经元或肌肉）中的蛋白质聚集体是关键因素的发展和发展神经退行性疾病和肌病的发展是衰老细胞的细胞标志。而蛋白质骨料疾病具有共同特征，但广泛认为导致蛋白质聚集的分子途径不能是用单个机制解释。在引起肌病的蛋白质聚集疾病中总体趋势已经出现，其中汇总的蛋白质和细胞器积聚在区域没有肌肉组织。但是，启动Z-Disk的细胞和机械触发器崩解和肌纤维位移尚不清楚。在这里，我们在保守的果蝇基因是发现导致细胞和分子机制的切入点蛋白质聚集和最终使用肌肉作为模型细胞类型的细胞变性。总体而言，我们期望揭示未认可的方面，包括但不限于：有助于蛋白质的新成分；识别激酶活性的肌肉靶标；和确定自噬如何在清除蛋白质聚集体中合作。一个强大的遗传分析，生物化学，细胞生物学和实时成像方法的结合将解决这些问题。我们希望这个项目从根本上推进了我们的了解如何调节蛋白质降解以防止细胞变性和提供有关如何有效清除蛋白质聚集体以减少疾病的新见解国家。