Cells sense a wide variety of mechanical inputs from their environment that drive processes such as growth, migration, synthesis, and inflammation. Integrin based adhesions form the basis for extracellular matrix mechanosensing and remodeling. However, they are just one linkage in a series of force networks that allow for transmission and sensing within the cell. Extracellular matrix (ECM) forces are directly transmitted through force sensitive focal adhesion adaptor molecules (talin, vinculin) to the force generating actomyosin cytoskeleton which connects to the nuclear envelope via the linker of nucleoskeleton and cytoskeleton (LINC) complex (nesprin, sun, lamin). While the core components of many mechanosensing networks have been well described over the last ~30 years, there remains gaps in our understanding of the internetwork transmission of forces and its importance in activation of downstream signaling. We use a variety of fluorescence imaging techniques to disect force transfer networks within the cell that drive mechanotransduction.
Dynamic Molecular Forces
While cells do eventually reach steady state with regards to a given mechanical input (stiffness, stretch, fluid shear stress), the process of sensing itself occurs through a dynamic network of proteins on the molecular scale. While studying mechanosensitive pathways using downstream readouts (translocation, transcription, protein expression) provides an understanding of what the cells do in response to a given stimulus, it does not provide the upstream molecular mechanisms by which this occurs. Realistically, it is these upstream biophysical events, at the molecular scale, that will provide a clear picture of mechanosensing. Our techniques enable us to measure forces and dynamics in living cells.
Mechanosensing plays a critical role in tissue homeostasis, which when perturbed often results in a fibrotic disease process. These fibrotic diseases are the result of tissue remodeling that drives a progressive and irreversible stiffening of the extracellular matrix. The normal homeostatic processes that maintain tissue mechanical properties under healthy conditions require both positive and negative feedback mechanisms. We study how post translational regulation through miRNAs provides negative feedback that allows for tissue homeostasis.