Full sail ahead: How do cells sense and decode flow? 

Abstract

We propose a unique multi-pronged and interdisciplinary effort to quantitatively define and predict how cells sense and respond to flow. The flow responses of endothelial cells (which form the inner surface of mammalian blood vessels) underly multiple important biological processes, such as cardiovascular health and embryonic development. However, despite decades of research, the physical and molecular mechanisms that cells use to sense flow and translate this mechanical stimulus into intracellular molecular responses are currently unknown. We hypothesize that flow-mediated reorganization of proteins at the surface of cells (similar to sailboats responding to wind) not only encodes information about flow speed and direction, but also initiates intracellular signaling. To confirm this hypothesis, we will complete experiments that combine fundamental fluid mechanics and lipid physics (Honerkamp-Smith lab) with cell signaling and membrane protein biochemistry (Thévenin lab). Our strategy is to conduct parallel experiments in both living cells and reductionist model systems, enabling us to create quantitative, predictive models while ensuring that our work is biologically relevant. While the model protein system studied here (glypican-1) is specific to endothelial cells, the principles of fluid mechanics that we will uncover are universal. We therefore anticipate that our models will be applicable to multiple cell lines and flow conditions and will lay the groundwork for future research avenues. We also expect that our work will provide transformative biological details and relevant physiological insights into different cardiovascular pathologies and cancers. Throughout this project, interdisciplinary training will be accomplished by involving undergraduate and graduate students from both groups at every level of research, from experimental design to data analysis and manuscript writing. 

 

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