FOR 2743:  Mechanical Stress Protection

• Subject Area: Biology
• Term: since 2018
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 388932620

Cell survival, tissue integrity and organismal health depend on the ability to maintain functional protein networks even under conditions that threaten protein integrity. Protection under such stress conditions involves the adaptation of folding and degradation machineries, which help to preserve the protein network and facilitate the refolding or disposal of damaged proteins. In multicellular organisms, cells are permanently exposed to stress resulting from mechanical forces and their homeostasis relies on dedicated stress protection systems. Mechanical stress protection operates during cell differentiation, adhesion and migration, and is of particular importance for maintaining tissues such as skeletal muscle, heart, lung, kidney, skin and vasculature. Yet, underlying molecular mechanisms have not been comprehensively studied. In an unprecedented multi-disciplinary approach, the research unit combines mechano- and cell biology, kidney, muscle and exercise physiology, molecular immunology and worm and mouse genetics. State-of-the-art technology will be used to apply mechanical stress in a highly defined manner to isolated cells and tissues, genetically tractable model organisms and human subjects. Force-induced alterations of protein folding and degradation machineries will be investigated through biochemical, cell biological, proteomic and genetic methods. This will allow us to identify chaperone and degradation systems dedicated to the handling of mechanically unfolded and damaged proteins, and to elucidate the regulation of these systems under mechanical stress. Based on the investigation of different cell types and tissues general protection mechanisms as well as more specialized responses will be revealed. The research unit will close an existing gap in the national and international research landscape between the analysis of force-generating, -bearing and -transducing structures in the field of mechanobiology and the characterization of stress protection pathways in the context of proteostasis research, so far focussing mainly on heat, oxidative and proteotoxic stress. The proposed work will establish fundamental principles of mechanical stress protection in multicellular organisms and will reveal the relevance of these processes for diseases such as muscle weaknesses, immune deficiencies and kidney failure.

• DFG Programme: Research Units
• International Connection: Poland

Projects

• Communication of mechanical cues to the stress response in epidermal cells (Applicant Niessen, Carien )
• Coordination Funds (Applicant Höhfeld, Jörg )
• Function and regulation of podin proteins under mechanical stress in muscle (Applicant Fürst, Dieter O. )
• Function and regulation of the BAG3 chaperone network under mechanical stress (Applicant Höhfeld, Jörg )
• Investigating mechano-protective mechanisms in human skeletal muscle (Applicants Bloch, Wilhelm ;  Gehlert, Ph.D., Sebastian )
• Mechanical stress-induced pathomechanisms in BAG3-associated myopathies (Applicant Hesse, Michael )
• Mechanical stress protection at the kidney filtration barrier (Applicants Benzing, Thomas ;  Rinschen, Markus )
• Protein phosphatases as essential regulators of the mechanical stress response (Applicant Köhn, Maja )
• Regulation of kinase-substrate networks in muscle cells under mechanical stress (Applicant Warscheid, Bettina )
• Regulation of small GTPase signalling networks and chaperone-assisted selective autophagy through mechanical forces in leukocytes and cardiomyocytes (Applicants Kolanus, Waldemar ;  Wachten, Dagmar )
• Regulation of the BAG3 chaperone network under mechanical stress (Applicants Höhfeld, Jörg ;  Köhn, Maja )
• Stress-induced myosin folding and assembly mechanisms (Applicant Hoppe, Thorsten )
• Tension induced autophagosome formation: substrates and mechanisms (Applicants Hoffmann, Bernd ;  Huesgen, Pitter )

• Spokesperson: Professor Dr. Jörg Höhfeld