Unraveling the propagation and repercussions of localized perturbations within tissues

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The goal of this proposal is to uncover how important signals travel between cells in epithelial tissues that form the lining of most animal organs. This communication is essential for maintaining healthy tissues, wound healing, and responding to infection and cancer. The project will employ a multidisciplinary combination of experimental and modeling approaches, and will provide opportunities for education, training, and public engagement. These broader impact activities include; 1) developing a course that would allow students to study multi-cellular interactions, 2) provide interdisciplinary training for the next generation of scientists, 3) allow for undergraduate internships for summer research experience, 4) create web-modules on the topic for citizen scientists, and 5) develop museum exhibits related to synthetic biology and cell-to-cell communication.This project aims to gain quantitative insight into how localized changes in a tissue propagate and impact tissue signaling and physiology. In particular, using an integrated experimental and computational approach, we will study how cAMP/PKA, Ca2+ and ERK signaling is coordinated within an individual epithelial cell, and how signals emanating from these pathway propagate from one cell to others in a tissue. Optogenetic tools will be developed to apply spatially and temporally precise perturbations to these pathways in designated single cells within a tissue, and then measure the resulting signaling and transcriptional activities in the sender cells where perturbations are initiated as well as receiver cells that sense the propagated perturbation. Emergent phenotypic repercussions of such perturbations, such as cellular mobility, will be assessed. To organize and interpret the data, generalize findings, and design maximally informed experiments, mathematical models that uniquely consider the tissue geometry and impact of spatial dimensions and heterogeneity on interactions within cell groups will be constructed. This multidisciplinary approach will allow for the generation of a quantitative understanding of the fundamental principles of collaboration in cell communities and the modalities by which local perturbations propagate and impact tissue physiology. This project is funded by the Systems and Synthetic Biology Program in the Division of Molecular and Cellular Biosciences.