Nuclear force feedback as rheostat for actomyosin tension control

Ageing manifests itself on multiple levels in the body. Many cell types, such as blood vessel and adjacent cells are subject to constant mechanical challenges due to blood flow and constriction. In cells, ageing and pre-mature ageing syndroms such as Progeria cause several changes that make them more prone to damage when they are put under strain. In this project we are going to investigate how cells regulate their responds to strain and why this does not work in aged cells. We have found that the cytoskeleton, the scaffold that keeps cells in shape and motile, is under more tension that experience symptoms of ageing. This leads to decreased ability to respond to varying outside forces that are applied onto the cells and often causes cell death. In this application we will investigate the cause of this reduced adaptability to force. This will help in understanding the changes that ageing causes in cells and potentially will give rise to new avenues of research into developing treatments for these symptoms.

This proposal will identify how nuclear force coupling regulates the cellular response to mechanical forces and how dysregulation of this process leads to pathologies associated with the pre-mature ageing disease Hutchinson Gilford Progeria Syndrome (HGPS). The actin cytoskeleton and actomyosin contractility are kept at a dynamic equilibrium to ensure a rapid response to mechanical challenges. The role of actomyosin mediated nuclear force transduction in this process is increasingly becoming apparent. Levels of tension applied on the nucleus regulate nuclear import/export, chromatin condensation, chromosome localisation and consequently gene expression. The nuclear lamina can also act as a signalling platform for the cell in response to mechanical strain. But how the nuclear lamina is involved in controlling the regulation of actomyosin tension is currently unknown. We can show that primary HGPS patient cells show higher levels of actomyosin tension, but less force applied on the nucleus when compared to age matched donors. We postulate that this nuclear force uncoupling leads to phenotypes associated with HGPS, like changes in the nuclear lamina that affect chromatin dynamics, nuclear transport and mechanical properties that reduce cellular fitness in response to stress. The project aims to delineate the cytoskeletal signalling pathways leading to effective nuclear force coupling; investigate the role alterations in the nuclear lamina play in response to force application and study the implication of increased actomyosin tension on cellular resilience to stress.