Characterization of single-cell dynamics that lead to collective behaviors

描述（由申请人提供）：这项工作的目标是了解单细胞信号传导动力学如何有助于多细胞系统（如社会性阿米巴Dictyosteelium discoideum）中集体行为的协调。在饥饿期间，变形虫分泌信号分子cAMP，并将其用作细胞聚集成多细胞生物体的线索。这些信号分子动力学可以在单个变形虫中使用野生型和突变细胞中的荧光传感器来测量。通过将它们限制在微流体装置中，变形虫可以暴露于空间和时间变化的微环境中，以测量这些变化如何影响信号传导。结合这些技术，该提案的目标是（1）显示发育过程中的单个网骨细胞是可兴奋系统，并开发其信号动力学的定量模型，以准确预测其行为和（2）识别单细胞cAMP信号网络中的反馈机制。从长远来看，这项工作将为描述基于单细胞动力学的集体行为协调的多细胞模型铺平道路。这样的模型将有助于确定解释生物系统如何协调集体行为并从单细胞控制行为过渡到多细胞控制行为的普遍原则。扩大我们对这些原则和反馈的理解，最终将使我们能够找到控制这些行为的新方法，并可能为依赖集体行为来协调其进展的疾病揭示新的药物和治疗目标。

DESCRIPTION (provided by applicant): 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.