The ultimate goal of the Cell and Molecular Mechanobiology Lab (CMML) is to understand, on a molecular level, how mechanical cues from the environment are detected, integrated, and manipulated by cells to dictate physiological and patho-physiological responses important in vascular biology, cancer biology, and tissue engineering approaches. Initially we will focus on how applied forces affect vascular smooth muscle cells to mediate atherosclerotic lesion formation and how molecular forces in cellular adhesion structures mediate cell migration. To accomplish these goals, we utilize an inter-disciplinary approach combining techniques and principles from engineering, optical microscopy, automated image analysis, molecular biology, biological physics, computational modeling, and biomaterials science.
As the heart pumps, blood flows and exerts forces on the cells of the vasculature. These forces are critical to normal vascular cell behavior and are important factors in diseases like atherosclerosis and hypertension. However the processes by which mechanical signals (i.e. force and tension) are converted into biochemical signals interpretable by cells are not well understood. Often cells respond to mechanical signals from the environment by altering their structure. This is largely mediated by changes in protein dynamics or signaling that lead to alterations in various sub-cellular structures including focal adhesions, the linkages between the extracellular environment and force-generating cytoskeleton. A primary limitation has been the inability to determine the effects of molecular forces on protein behavior and function. The CMML has pioneered a microscopy-based approach allowing the visualization of the spatio-temporal dynamics of forces across specific proteins in living cells. Initial efforts have focused on proteins, such as vinculin, that are components of the physical link between the cytoskeleton and the extracellular environment. Utilizing this sensor we showed that forces across vinculin lead to enhanced focal adhesion growth.
Current projects include identifying the biochemical signaling pathways mediating the force-based regulation of focal adhesions and cell-cell contacts, the structures that mediate the mechanical linkages between the extracellular environment and other cells respectively.This work will provide molecular insight into the force-sensing abilities of vascular smooth muscle cells, which mediate the myogenic response and are important in the development of atherosclerotic lesions. Also we will create novel sensors to study the role of molecular forces in cell-cell contact assembly. The maintenance of these linkages is necessary for proper mechano-chemical coupling between cells. Conversely, the disruption or alteration of these linkages is a key step in the metastasis of cancer cells. Thus, our results will provide critical molecular details that will further the understanding of fundamental physiological processes and inform studies seeking new drug targets and tissue engineering approaches for the treatment of mechanosensitive diseases.