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

使用图像引导合成控制剖析原位骨髓信号传导

• 批准号: 10794433
• 负责人: Miles A Miller
• 金额: $ 14.11万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-06-01 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10794433
• 关键词: Address; Adoptive Cell Transfers; Affect; Anti-Inflammatory Agents; Biological; Cells; Data; Decision Making; Dendritic Cells; Diffusion; Disease; Dissection; Drug Targeting; Drug resistance; Feedback; Genetic; Goals; In Situ; Macrophage; Malignant Neoplasms; Malignant neoplasm of ovary; Microscopy; Modality; Molecular; Monitor; Myelogenous; Myeloid Cells; Nanotechnology; Pathology; Reaction; Signal Transduction; System; Systems Biology; Technology; Therapeutic; Time; Tissue atlas; Tissues; cell behavior; cell community; cell motility; design; flexibility; image guided; in vivo imaging; information processing; insight; intercellular communication; monocyte; novel; novel therapeutic intervention; real time monitoring; response; synthetic biology; technology platform; tumor microenvironment

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.

系统生物学的主要目标是理解分子电路如何控制信息 多细胞社区的处理和决策。增长且在很大程度上描述性的单细胞 组织和病理的地图集已经开始提供丰富的洞察力和空间组织 在微环境中，了解与此类关系的影响仍然是一个挑战 数据。一个单元的信号传导状态如何影响其邻居的信号状态？这个简单的问题很复杂 通过在组织中的反应/散射运输，基于细胞对信号的反应和动态的反馈回路 细胞迁移。尽管有这种复杂性，但了解多尺度间交流的原理 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，它有 很难直接解析组织中的信号传播，因为技术差距限制了我们的能力 在天然疾病微环境中操纵和监测原位细胞行为。 我们的建议通过利用体内成像，纳米技术的最新进展来解决这些问题 和合成生物学，以生成图像引导的操作，实时监控和 系统级别的微环境壁ches中信号传播的分析。作为初始申请，我们 将使用此框架了解髓样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，由于它们高度与耐药性有关 通过靶向药物或自适应细胞疗法，尚不清楚它们在光谱中的信号如何 促和抗炎性状态可以在空间和及时扩散到相邻的细胞。虽然这个 项目将产生对髓样信号传播的基本见解，我们还旨在扩展图像 - 带有潜在治疗应用的转换方式的遗传重编程。 实现这些目标的技术集成的新颖集成有望使潜水员具有灵活性和有用 髓样细胞在癌症及其他地区起作用的生物应用。