Connecting Single-Cell Signaling Dynamics to Multicellular Decision Making

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SUMMARY Cures for many diseases and injuries have remained elusive because the systems they affect are highly adaptable multicellular collectives that harness biochemical communication to reprogram themselves to circumvent our treatment strategies. The goal of my research program is to identify how single cells interpret their environments and modulate their behaviors to control these multicellular decisions. Our current understanding of this connection has been limited due to the conceptual and technological challenges presented by connecting the small-scale, fast dynamics inside single cells to larger-scale behaviors unfolding over hours and days in cellular populations. During this award, we will address these challenges and focus on resolving several key gaps in our understanding, specifically (1) identifying single-cell regulatory mechanisms for modulating population-wide behaviors and (2) elucidating how the interplay between signaling and mechanics drives cellular populations to work together to remodel themselves. To enable us to directly link single-cell dynamics to population-wide decision making, we are developing and implementing new technologies for simultaneous quantitative visualization and control of intra- and intercellular biochemical dynamics driving these decisions. These techniques, in combination with quantitative modeling, will allow us to make causal links between intracellular signaling and multicellular behaviors. Our work will be performed in a classic model organism for collective behaviors, the social amoeba Dictyostelium discoideum, as well as a biomimetic wound healing model where we can directly link intracellular signaling to mechanical environmental cues. The tools we develop in these systems to link signaling dynamics to population behaviors will also enable us to interrogate these behaviors and develop models of these behaviors with real predictive power. With our new predictive understanding of the single-cell dynamics used to coordinate collectives and by demonstrating we can control these behaviors ourselves, we will be laying the groundwork for reprogramming these behaviors for transformative new disease and injury treatments.