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 多细胞群落中的信息处理和决策过程。一个不断增长的，主要是描述性的单细胞 组织和病理学图谱已经开始提供对组成和空间组织的丰富见解 然而，要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状态如何影响它的邻居？这个简单的问题很复杂 通过组织中的反应/扩散转运，基于细胞对信号传导的反应的反馈回路，以及动态 细胞迁移尽管如此复杂，理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的疗法的关键组成部分。不幸的是， 由于技术差距限制了我们的能力， 在原生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，以生成用于图像引导操作、实时监测和 微环境生态位内信号传播的系统级分析。作为初步应用，我们 我将使用这个框架来了解髓样极化信号是如何影响肿瘤的 转移性卵巢癌的微环境。我们特别关注单核细胞来源的树突状细胞 和巨噬细胞，因为它们与耐药性高度相关，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越光谱 促炎和抗炎状态的相互作用可以在空间和时间上传播到邻近的细胞。虽然这 项目将产生骨髓信号传播的基本见解，我们还旨在扩展图像- 引导基因重编程为具有潜在治疗应用的预防相关模式。 为实现这些目标而进行的新的技术整合有望成为灵活和有用的， 骨髓细胞在癌症及其他方面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.