QSB: Integrated Dynamics of Cell-cell Communication

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PROJECT SUMMARY (JOHN YIN, 0331337)Intellectual merit: Cell-cell communication plays a central role in the control of cell growth, regulation of cell differentiation, defense against microbial invaders, and unified function of tissues and organs. While progress has been made toward identifying molecular mechanisms through which cells create and respond to communication signals, it is less well understood how cell communication networks function as integrated units. To address this need, we have devised an experimental system that enables us to observe the dynamics of cell-cell communication in vitro. Specifically, we track the progressive development of an anti-viral state in cells as they respond to signals produced by virus-infected cells. Our long term goal is to build an integrated molecular-level understanding of this process. Toward this end, we propose here to formulate and refine an initial model for the process. The model will incorporate and integrate information at multiple levels using structured cell population balances. At the intracellular level these balances will allow us to account for the kinetics of virus growth, signal production, and the inhibitory effects of signal on a single-cycle of virus growth. At the extracellular level, the balances will account for the spatial spread by diffusion of signals and virus progeny, the effects of signaling on resources in uninfected cells, and, finally, the gradual attenuation of virus spatial propagation distributed over many cycles of virus growth. The model will build primarily on established molecular mechanisms drawn from the literature, and it will be refined by experiments we perform on single-cycle virus growth and spatially spreading virus infections. Our model will be used to identify parameters or groups to parameters that govern the effects of cell-cell signaling on virus containment. Further, it will serve as a foundation to identify novel anti-viral strategies based on an integrated systems-level understanding of cell and virus dynamics. Broader impact: This proposed study is highly interdisciplinary. It will employ computer simulations to characterize the intra- and extracellular dynamics of virus growth and cell-cell signaling. The cross-disciplinary experience gained by students and co-workers who pursue this research, as well as the textbook sections, refereed publications, technical presentations and course materials that result from this work, will advance research and education in cell-cell communication and, more broadly, in systems biology.