Molecular mechanisms of the mechanical interaction between the cell nucleus and the actin cytoskeleton

Objetivo

The cytoskeleton plays a pivotal role in growth, development, and disease by sensing mechanical stress and mediating structural remodeling and cell functional responses. The cytoskeleton, which is linked directly to the nuclear lamina and thereby to chromatin, has recently been proposed to impact on chromatin remodeling and transcriptional activity. However, the mechanisms and biological consequences of force-dependent chromatin remodeling have remained elusive. Within this context main goals for my project are 1) to characterize nuclear rheology and stress transmission over the nuclear-cytoskeletal linkage, 2) to identify molecular mechanisms of force transmission into the nucleus and 3) to develop a numerical model of cell contractility and remodeling to systematically and quantitatively investigate the stress transmission to the nucleus to test my hypothesis that global force application to the nucleus can control nuclear mechanics, chromatin structure and transcriptional activity in a predictable, biologically meaningful way.
This interdisciplinary project, integrating both cell/molecular biology of genome regulation and bioengineering, will advance our understanding of cellular mechanosensing and mechanotransduction, and carries therefore a strong transformative potential for discovering new strategies to mitigate many diseases where the interplay of mechanics and biochemistry are critical.