Coordination Funds

多细胞生物体的细胞永久地暴露于由机械力引起的应力。在这种情况下，生物体健康和蛋白质稳态（蛋白质稳态）取决于蛋白质折叠和降解系统的适应，这些系统处理力未折叠和受损的蛋白质。为了阐明机械应力保护，研究单位实施了一种高度跨学科的方法，将机械和细胞生物学，肾脏，肌肉和运动生理学，分子免疫学以及蠕虫和小鼠遗传学整合在一起。在靶向研究中，通过无偏转录组学和蛋白质组学分析，在分离的细胞和组织、遗传上易于处理的模式生物和人类受试者中发现了机械保护机制。我们的工作导致了机械敏感的客户端蛋白，中央保护因子和关键的调控成分的鉴定。阐明了所涉及的激酶和磷酸酶依赖性信号传导网络，并定义了与机械保护相关的可逆磷酸化事件。这些研究结果将指导进一步分析的蛋白质稳定系统的机械应力保护和他们的力依赖性调节，通过生化，细胞生物学，生物物理，蛋白质组学和遗传学的方法。第二个供资期的重点将是确定不同组织和生物体之间的机械保护系统和信号通路的特征。这项工作将揭示多细胞生物中机械应力保护的基本原理，并建立它们与人类生理学和病理生理学的相关性。

Cells of multicellular organisms are permanently exposed to stress resulting from mechanical forces. Organismal health and protein homeostasis (proteostasis) depend in this situation on the adaptation of protein folding and degradation systems, which handle force-unfolded and damaged proteins. To elucidate mechanical stress protection, the research unit has implemented a highly interdisciplinary approach that integrates mechano- and cell biology, kidney, muscle and exercise physiology, molecular immunology, and worm and mouse genetics. In targeted studies and through unbiased transcriptomic and proteomic analysis mechano-protective mechanisms were uncovered in isolated cells and tissues, genetically tractable model organisms, and human subjects. Our work led to the identification of mechano-sensitive client proteins, central protection factors, and key regulatory components. Involved kinase and phosphatase dependent signalling networks were elucidated and reversible phosphorylation events relevant for mechano-protection were defined. These findings will direct the further analysis of proteostasis systems essential for mechanical stress protection and their force-dependent regulation through biochemical, cell biological, biophysical, proteomic and genetic methods. A focus for the second funding period will lie on the characterization of identified mechano-protection systems and signalling pathways across different tissues and organisms. The proposed work will reveal fundamental principles of mechanical stress protection in multicellular organisms and establish their relevance for human physiology and pathophysiology.