Dissection of in situ myeloid signaling using image-guided synthetic control

系统生物学的一个主要目标是理解分子电路如何控制信息 多细胞群落中的处理和决策。不断生长且具有描述性的单细胞 组织和病理图谱已开始提供对组成和空间组织的丰富见解 微环境的影响，但从这些微环境中理解因果关系仍然是一个挑战 数据。一个细胞的信号传导状态如何影响其邻近细胞的信号传导状态？这个简单的问题却很复杂 通过组织中的反应/扩散传输、基于细胞对信号传导的反应的反馈回路以及动态 细胞迁移。尽管存在这种复杂性，但了解多尺度细胞间通讯的原理 有望成为设计基于细胞和信号传导的疗法的关键组成部分。不幸的是，它有 由于技术差距限制了我们的能力，因此很难直接解析组织中的信号传播 在天然疾病微环境中原位操纵和监测细胞行为。 我们的提案通过利用体内成像、纳米技术、 和合成生物学来生成图像引导操作、实时监测和 微环境生态位内信号传播的系统级分析。作为初始应用程序，我们 将使用这个框架来了解骨髓极化信号如何影响肿瘤 转移性卵巢癌的微环境。我们特别关注单核细胞衍生的树突状细胞 和巨噬细胞，因为它们与耐药性密切相关，所以它们在治疗上被操纵 通过靶向药物或过继细胞疗法，目前尚不清楚它们的信号传导如何跨谱 促炎和抗炎状态可以随着空间和时间传播到邻近细胞。虽然这 该项目将产生对骨髓信号传播的基本见解，我们还旨在扩展图像- 指导基因重编程为具有潜在治疗应用的翻译相关模式。 实现这些目标的新颖的技术集成有望灵活且适用于不同的领域 骨髓细胞在癌症及其他疾病中发挥作用的生物学应用。

A major goal of systems biology has been to comprehend how molecular circuitry governs information processing and decision-making in multicellular communities. A growing and largely descriptive single-cell atlas of tissues and pathologies has begun providing rich insight into the composition and spatial organization of microenvironments, yet it remains a challenge to understand cause-and-effect relationships from such data. How does the signaling state of one cell affect that of its neighbors? This simple question is complicated by reaction/diffusion transport in tissue, feedback loops based on cellular response to signaling, and dynamic cell migration. Despite this complexity, understanding principles of multi-scale intercellular communication promises to be a key component in designing cellular- and signaling-based therapies. Unfortunately, it has been difficult to directly parse signal propagation in tissue because technological gaps have limited our ability to manipulate and monitor cell behavior in situ within native disease microenvironments. Our proposal addresses these questions by leveraging recent advances in in vivo imaging, nanotechnology, and synthetic biology to generate a framework for image-guided manipulation, real-time monitoring, and systems-level analysis of signal propagation within microenvironmental niches. As an initial application, we will use this framework to understand how myeloid polarization signaling influences the tumor microenvironment in metastatic ovarian cancer. We focus in particular on monocyte-derived dendritic cells and macrophages, since they are highly implicated in drug resistance, they are therapeutically manipulated via targeted drugs or adoptive cell therapies, and it remains unclear how their signaling across the spectrum of pro- and anti-inflammatory states can spread to neighboring cells over space and in time. Although this project will yield fundamental insights into myeloid signaling propagation, we also aim to extend image- guided genetic reprogramming to translationally-relevant modalities with potential therapeutic application. The novel integration of technologies to achieve these goals promises to be flexible and useful for diverse biological applications where myeloid cells play a role, in cancer and beyond.