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

ended

Mechanical forces drive fundamental physiological functions in living organisms, yet it remains unclear how forces are transduced into intracellular biochemical signals. Mechanotransduction is a tightly regulated process, and its disruption often results in pathologies including tumorigenesis, chronic inflammation and fibrotic conditions. Crucially, recent studies have shown an important relationship between abnormal fibrosis and altered patterns of focal adhesion kinase (FAK) activity and cell adhesion. Prof. del Campo laboratory has pioneered the use of photo-triggerable ligands to spatiotemporally control cell adhesion and recently, Prof. García has demonstrated in vivo that spatiotemporal control of cell adhesion modulates fibrosis. In addition, Prof. García has demonstrated a strong relationship between cells adhesive force generation and FAK activation at individual focal adhesion (IFA). Despite the importance of FAK signalling in cancer and other pathologies, the mechanistic link between the FAK activity at individual focal adhesions and fibrosis remains elusive. To close this gap in our knowledge, there is a need to develop technologies capable of recapitulating dynamic force transmission at individual focal adhesions. This project aims to elucidate the molecular events that regulate FAK activity during force transmission and sensing of mechanical force at individual focal adhesions. I will combine novel molecular devices, light-activated cell-specific adhesive ligands and microscopy tools to in situ apply controlled forces at individual FA and measure cell responses in 2D, 3D and in vivo contexts. Importantly, FAK loss- and gain-of-function experiments will provide the functional importance of FAK during mechanotransduction. The fundamental investigation of mechanotransduction events will greatly advance our understanding of cell biology and inform future targets for fibrosis therapy, as mechanical forces is a driving factor in fibrosis progression.