MECHANO FIBROSIS · Regulation of mechanotransduction through motor-molecules activation of focal adhesion kinase in progressive fibrosis

Regulation of mechanotransduction through motor-molecules activation of focal adhesion kinase in progressive fibrosis

Mechanical forces arising from cell-ECM interactions are key regulators of tissue development, health, and fibrotic disease progression. Tissue fibrosis contributes to 45% of all deaths in the developed world and is characterized by progressive extracellular matrix (ECM) stiffening and altered patterns of cell adhesion signalling (i.e., focal adhesion kinase, FAK). Yet, studying dynamic ECM-Cell biophysical interactions with static structures, biochemically centric methodologies, and incomplete ECM-Cell descriptions presents an unprecedented challenge in tissue engineering and regenerative medicine (TERM). Focal adhesions (FAs), nanoscale complexes of structural and signalling molecules that link the extracellular matrix (ECM) to the cytoskeleton through integrin receptors, function as principal sites of mechanotransduction. Studies with contractility inhibitors, deformable substrates, and laser tweezers have established that force regulates FA assembly and signalling and identified key molecules in these mechanoresponses, yet very little is known about how forces are integrated into biochemical signalling. Most of our understanding of cell-ECM interactions comes from either cell population-based or ‘whole’ cell assays on static substrates of varying stiffness where the cell is viewed as in a ‘uniform’ stress state. These analyses provide only ‘averaged’ metrics that do not capture/reveal important relationships at the cell-ECM interface due to the heterogeneity of individual subcellular components. With this project, the fellow will decisively overcome the technical limitations of studying cell-ECM dynamics in fibrotic microenvironments by developing engineering tools and investigative in vivo models to examine the role of focal adhesion mechanobiology in tissue homeostasis and fibrosis disease progression. Conclusions of the Action: The MECHANO FIBROSIS project successfully developed and implemented a novel engineering tool, capable of applying forces to molecular bonds at the cell-ECM interface, demonstrating its utility in studying mechanotransduction at the molecular level. The project's findings have significantly advanced the understanding of cell-ECM interactions in healthy (soft) and fibrotic (stiff) environments, highlighting the importance of mechanical forces in cellular signaling and disease progression. The outcomes of this research have potential implications for developing new diagnostic and therapeutic tools for fibrotic diseases, thereby addressing a critical societal health issue.

Текст от CORDIS, на английски · Данни: CORDIS, © Европейски съюз