Toward an integrative understanding of mammalian cell motility

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There has been significant progress over the last few years in understanding many of the detailed dynamical mechanisms underlying mammalian cell motility. These include the role of focal adhesions, the spatio-temporal organization of actin flow, the response of the leading-edge membrane to actin polymerization and conversely the role of myosin minifilaments in creating contractile stress at the rear. It is now an opportune time to combine this knowledge into a mathematical model which can treat the morphodynamics of the whole cell, and correlate motion with both mechanical data (such as traction-force measurements) and sub-cellular signaling information (such as localization data for specific molecular players.) This proposal aims at constructing and validating such a model for endothelial cells. From the mathematics side, the novel element includes embedding all of the aforementioned processes into a moving cell geometry, enabled by the phase-field approach; the latter has shown its relevance in many moving boundary problems in fields ranging from solidification to multiphase fluid flow. Experimental data will be obtained by utilizing state-of-the-art microfluidic devices so as to provide controlled cell environments and will include the measurement of spatial patterns of signaling molecules (location and activation) as well as forces. Model predictions will be tested in a number of different cell lines and in cells subject to a variety of pharamacological treatments.Obtaining a quantitative understanding of cell motility is of importance for many critical biomedical systems, ranging from cancer metastases to inflammatory response to pathogens. Biophysical tools have reached the point where one can obtain high-quality data about various parts of the motility mechanism; for example, we can measure the forces exerted by the cell on the substrate on which it moves. At the same time, advances in computational modeling have shown how to tackle complex problems involving fluid flow and chemical reactions taking place inside a moving domain. Our proposal aims at combining these two capabilities, experimental biophysics and computational modeling to create a quantitative approach to the motion of a specific type of mammalian cell. Once successful, our methodology could be extended to other cell types and to cells moving in more complicated spaces. The eventual payoff would be both an increased fundamental understanding and an increased capability of affecting cell motility, perhaps to prevent cells from a primary tumor from establishing secondary colonies in target tissues.The proposal was submitted in response to the Joint DMS/NIGMS Initiative to Support Research at the Interface of the Biological and Mathematical Sciences. The grant is funded by the Program of Mathematical Biology of the Division of Mathematical Sciences and co-funded by the Program Physics of Living Systems in the Physics Division of NSF.