Connecting Single-Cell Signaling Dynamics to Multicellular Decision Making

总结 许多疾病和伤害的治愈方法仍然难以捉摸，因为它们影响的系统是 高度适应性的多细胞群体，利用生化通讯来重新编程， 规避我们的治疗策略我的研究项目的目标是确定单细胞如何解释 并调节它们的行为来控制这些多细胞决定。我们目前 由于概念和技术上的挑战，对这种联系的理解是有限的 通过将单个细胞内的小规模快速动态与更大规模的行为展开联系起来， 在细胞群中持续数小时和数天。在此次颁奖期间，我们将应对这些挑战，并专注于 解决我们理解中的几个关键差距，特别是（1）确定单细胞调节机制 用于调节群体范围内的行为，以及（2）阐明信号传导和 力学驱使细胞群体一起工作来重塑自己。使我们能够直接连接 单细胞动力学到全人群决策，我们资助的赠款支持开发和 实施新技术，用于同时定量可视化和控制细胞内和细胞间 生物化学动力学驱动这些决定。这一设备补充要求提供资金，以支持 高通量、高重现性的成像系统，以支持遗传编码工具的筛选， 成像条件来询问这些信号动力学。我们试图理解的行为发生在 小时和天，并调整量化和控制这些动态的新问题的工具，需要一个 高通量方法。我们在这些系统中开发的工具将信号动态与人口联系起来 行为也将使我们能够询问这些行为，并开发这些行为的模型与真实的 预测能力。这一补充将使我们能够发展一个新的预测理解的单一- 细胞动力学用于协调集体，并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奠定基础， 治疗，以及开发特征良好的工具箱，用于询问和控制这些行为， 多模型系统，我们将传播到更广泛的医学科学界。

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.