The tissues of the body stiffen with age and also with the progression of numerous diseases. It is now known that this change in stiffness can drive disease by causing cells within the tissue to adopt unhealthy behaviors. However, tissues do not stiffen uniformly. The tissues can develop numerous small foci of stiffness so that the stiffness varies markedly throughout. It is not yet known how cells respond to these distributed foci of stiffness that develop with age and disease. This award supports the research necessary to understand how the process of aging contributes to the development of stiffness foci and how these stiff foci alter cell function. The primary activity in this work will be on the development of mechanical stiffness foci within blood vessels and the evaluation of their effects on the cells within the blood vessel wall. However, this basic research will have a broad impact on current understanding of physiology and pathology throughout the body, as changes in tissue stiffness with age can occur in multiple different organ systems. As such, this work will have broad impact to society. The project involves techniques from cell biology, materials science, optics, and microfabrication. This multi-disciplinary approach coupled with research activities designed to involve diverse sets of researchers and students will help train engineers to think and work across disciplinary boundaries.
While "heterogeneity" is now appreciated as an important component of biology, the primary focus to-date has been on cell-to-cell molecular-level heterogeneities. However, heterogeneities also exist in the extracellular environment and have been largely overlooked. Many tissues display foci of mechanical stiffness - heterogeneities in stiffness that exist over just a few microns. This project will address the stiffness foci that develop in tissue and their effects on cell-cell adhesion and force generation. In this project, the major research goal is to characterize these foci and their biophysical effects on endothelial cell-cell adhesion using state-of-the-art tools including Atomic Force Microscopy (AFM), microfabrication, and ex vivo models. These studies have the potential to identify a novel mechanism by which age contributes to endothelial dysfunction. More importantly, this work will bring to light the role of mechanical heterogeneities within the matrix on cell biophysics. While the research here will be on the endothelium, it is expected that the results will be relevant to many tissues and pathologies including cancer and embryonic development where heterogeneities in mechanical properties also exist.
