Connecting Single-Cell Signaling Dynamics to Multicellular Decision Making

摘要 许多疾病和伤害的治愈仍然难以捉摸，因为它们影响的系统是 高度适应性的多细胞集合体，利用生化通信重新编程以 绕过我们的治疗策略。我的研究项目的目标是确定单个细胞如何解释 它们的环境并调节它们的行为来控制这些多细胞决定。我们目前的情况 由于概念和技术上的挑战，对这种联系的理解一直有限 通过将单个细胞内部的小规模、快速动态与展开的更大规模的行为联系起来 在蜂窝种群中持续数小时和数天。在这个奖项中，我们将应对这些挑战，并将重点放在 解决我们理解中的几个关键差距，特别是(1)确定单细胞调控机制 用于调节整个种群的行为，以及(2)阐明信号和信号之间的相互作用 机械学驱使细胞群体共同努力，重塑自己。使我们能够直接链接 将单细胞动力学转化为全人口决策，我们的资助基金支持发展和 实施细胞内和细胞间同时定量可视化和控制的新技术 推动这些决定的生物化学动力学。这项设备补充申请资金用于支持 高通量、高重复性的成像系统，以支持对基因编码工具和 成像条件，以询问这些信号动力学。我们试图理解的行为发生在 几个小时和几天，并使量化和控制这些动态的工具适应新的问题需要一个 高吞吐量方法。我们在这些系统中开发的将信号动态与种群联系起来的工具 行为也将使我们能够审问这些行为并开发这些行为的真实模型 预测能力。这一补充将使我们能够对单一的- 细胞动力学用来协调集体，通过展示我们可以自己控制这些行为， 为重新编程这些行为以应对变革性的新疾病和伤害奠定基础 治疗，以及开发特性良好的工具箱，以审问和控制这些行为在 我们将向更广泛的医学科学界传播多种模型系统。

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, our funded grant supports developing and implementing new technologies for simultaneous quantitative visualization and control of intra- and intercellular biochemical dynamics driving these decisions. This equipment supplement is requesting funding to support a high-throughput, highly-reproducible imaging system to support the screening of genetically-encoded tools and imaging conditions to interrogate these signaling dynamics. The behaviors we seek to understand occur over hours and days, and adapting tools for quantifying and controlling these dynamics to new questions requires a high-throughput approach. 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. This supplement will both allow us to develop a new predictive understanding of the single- cell dynamics used to coordinate collectives and by demonstrating we can control these behaviors ourselves, laying the groundwork for reprogramming these behaviors for transformative new disease and injury treatments, as well as develop well-characterized toolbox for interrogating and controlling these behaviors in multiple model systems that we will disseminate to the broader medical science community.