QSB: Integrated Dynamics of Cell-cell Communication

项目概述（JOHN YIN, 0331337）智力价值：细胞-细胞通讯在控制细胞生长、调节细胞分化、防御微生物入侵和组织器官统一功能中起着核心作用。虽然在识别细胞产生和响应通信信号的分子机制方面已经取得了进展，但人们对细胞通信网络如何作为一个整体单元发挥作用还不太了解。为了满足这一需求，我们设计了一个实验系统，使我们能够在体外观察细胞间通讯的动态。具体来说，我们追踪细胞中抗病毒状态的逐渐发展，因为它们对病毒感染细胞产生的信号作出反应。我们的长期目标是建立对这一过程的综合分子水平的理解。为此，我们在此建议为该过程制定和完善一个初始模型。该模型将使用结构化细胞种群平衡在多个层次上合并和集成信息。在细胞内水平上，这些平衡将使我们能够解释病毒生长、信号产生的动力学，以及信号对病毒生长单循环的抑制作用。在细胞外水平，这些平衡将解释信号和病毒子代扩散的空间传播，信号对未感染细胞资源的影响，最后，在病毒生长的许多周期中分布的病毒空间传播的逐渐衰减。该模型将主要建立在从文献中得出的已建立的分子机制上，并将通过我们对单周期病毒生长和空间传播病毒感染进行的实验来完善。我们的模型将用于识别控制细胞-细胞信号传导对病毒遏制作用的参数或参数组。此外，它将作为基于对细胞和病毒动力学的综合系统级理解来确定新的抗病毒策略的基础。更广泛的影响：本研究是高度跨学科的。它将采用计算机模拟来表征病毒生长和细胞-细胞信号传导的细胞内和细胞外动力学。从事这项研究的学生和同事所获得的跨学科经验，以及由这项工作产生的教科书部分、评审出版物、技术演示和课程材料，将推动细胞-细胞通信的研究和教育，更广泛地说，是系统生物学的研究和教育。

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.