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.

系统生物学的一个主要目标是理解分子电路如何管理信息。 多细胞社区中的处理和决策。一种不断增长的、基本上具有描述性的单细胞 组织和病理地图集已经开始提供对构成和空间组织的丰富洞察力 然而，从这样的微环境中理解因果ff等关系仍然是一个挑战 数据。一个ff的信令状态如何影响其邻居的信令状态？这个简单的问题很复杂 通过反应/扩散ff在组织中的运输，基于细胞对信号的反应的反馈循环，以及动态 细胞迁移。尽管有这种复杂性，理解多尺度细胞间通信的原理 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，它已经 由于技术差距限制了我们的能力，ffi一直崇拜直接解析组织中的信号传播 在自然疾病微环境中就地操纵和监测细胞行为。 我们的提案通过利用活体成像、纳米技术、 和合成生物学，以生成用于图像引导操作、实时监控和 微环境中信号传播的系统级分析。作为最初的申请，我们 将使用这个框架来理解fl中的髓系极化信号如何利用肿瘤 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。 巨噬细胞，因为它们与抗药性高度相关，所以它们被治疗操纵 通过靶向药物或采用细胞疗法，目前尚不清楚它们是如何通过光谱传递信号的 支持和反对fl的炎性状态可以在空间和时间上传播到邻近的细胞。虽然这件事 项目将对髓系信号传播产生基本的见解，我们的目标也是扩展图像- 引导基因重新编程到翻译相关的模式，具有潜在的治疗应用。 实现这些目标的新技术集成有望成为fl可扩展的，并对不同的 髓系细胞在癌症和其他疾病中发挥作用的生物学应用。