PROJECT SUMMARY The overall objective of my research program is to define fluid as an integral component of the cellular microenvironment and to better understand how movement of fluid in the microenvironment impacts cell and tissue processes. My laboratory employs a multidisciplinary approach merging microfabrication techniques and microfluidic devices, computational fluid dynamics, and cellular and molecular biology to define the mechanisms by which cells sense and respond to fluid flow. We are specifically interested in how forces from moving fluids impact cell adhesion and effector signaling, and to further our overall goals, we have identified three specific interests: (1) resolving the forces that moving fluids impart on cells, (2) identifying the molecular machinery that transduces these forces into biological responses, and (3) determining how molecular scale transduction is coordinated into a tissue scale response. While my training focused on understanding fluid flow and transport in cancer and the vasculature, my independent research laboratory seeks to focus on tissues and processes in which the effects of fluid transport are not as well defined, with an emphasis on development and morphogenesis. In line with these objectives, over the next five years, the specific goals of my research laboratory are to: (1) engineer cell surface receptors to better understand how the highly conserved Notch family receptors sense fluid flow, (2) map forces and cellular responses to flow through porous media by developing novel, integrated microfluidic and computational approaches, (3) develop a new class of microfluidic devices to recapitulate the native microenvironment using human-derived cells and matrix. The results of this research and the integration of the enabling technologies will contribute to the overall objectives of my research program of defining the scope and general principles of fluid forces in the cellular microenvironment, illuminating the mechanisms by which cells respond to these forces, and providing new tools for broader application among the mechanotransduction community. Furthermore, the technology developed within this proposal will form the basis for developing future disease models for mechanistic and translational applications.