The goal of this work is to understand how single-cell signaling dynamics contribute to the coordination of collective behaviors in multicellular systems such as the social amoeba Dictyostelium discoideum. During starvation, the amoebae secrete the signaling molecule cAMP and use it as a cue for the cells to aggregate into a multicellular organism. These signaling molecule dynamics can be measured in individual amoeba using fluorescent sensors in wild type and mutant cells. By confining them to microfluidic devices, the amoebae can be exposed to spatially and temporally varying microenvironments to measure how these changes influence signaling. Combining these techniques, this proposal's targets are (1) to show that single Dictyostelium cells during development are excitable systems, and to develop a quantitative model of their signaling dynamics that accurately predicts their behavior and (2) to identify feedback mechanisms in the single-cell cAMP signaling network. In the long term, the proposed work will pave the way for a multi-cellular model that describes the coordination of collective behavior based on single-cell dynamics. Such a model would aid in identifying universal principles that explain how biological systems coordinate collective behavior and undergo the transition from single- to multicellular-controlled behaviors. Expanding our understanding of these principles and feedbacks will ultimately allow us to find new ways to control these behaviors, potentially revealing new drug and treatment targets for diseases that rely on collective behavior to coordinate their progression.

Public Health Relevance

Collective behaviors that emerge in large cell populations are ubiquitous in biology and critical to the survival of these systems. This proposal's goal is to understand the dynamics of single cells during the coordination of collective behaviors. This will be accomplished through quantitative modeling and identification of positive and negative feedback mechanisms in the signaling circuits of individual cells. The ultimate goal of this work is to use understanding of coordinated cell behavior to develop novel therapies that can interrupt tumor growth and development or reprogram other disease mechanisms whose progress depends on collective cellular behaviors.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Postdoctoral Individual National Research Service Award (F32)
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Special Emphasis Panel (ZRG1-F05-D (21))
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Flicker, Paula F
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Princeton University
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United States
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Tarnita, Corina E; Washburne, Alex; Martinez-Garcia, Ricardo et al. (2015) Fitness tradeoffs between spores and nonaggregating cells can explain the coexistence of diverse genotypes in cellular slime molds. Proc Natl Acad Sci U S A 112:2776-81
Noorbakhsh, Javad; Schwab, David J; Sgro, Allyson E et al. (2015) Modeling oscillations and spiral waves in Dictyostelium populations. Phys Rev E Stat Nonlin Soft Matter Phys 91:062711