Coordination Funds

多细胞生物的细胞长期暴露在由机械力引起的应力下。在这种情况下，机体健康和蛋白质稳态（proteostasis）取决于蛋白质折叠和降解系统的适应性，这些系统处理力展开和受损的蛋白质。为了阐明机械应力保护，该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、蠕虫和小鼠遗传学结合在一起。在有针对性的研究中，通过无偏倚的转录组学和蛋白质组学分析，在分离的细胞和组织、遗传易感的模式生物和人类受试者中发现了机械保护机制。我们的工作导致鉴定机械敏感的客户蛋白，中心保护因子和关键的调控成分。参与激酶和磷酸酶依赖的信号网络被阐明，可逆磷酸化事件相关的机械保护被定义。这些发现将指导通过生化、细胞生物学、生物物理学、蛋白质组学和遗传学方法进一步分析机械应力保护及其力依赖调节所必需的蛋白质平衡系统。第二个资助期的重点将放在已确定的机械保护系统的特征和不同组织和生物体的信号传导途径上。提出的工作将揭示多细胞生物机械应力保护的基本原理，并建立其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.