Understanding Immune-Stromal Interactions in Tissue Homeostasis and Inflammation

了解组织稳态和炎症中的免疫基质相互作用

• 批准号: 10714085
• 负责人: XU ZHOU
• 金额: $ 44.25万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-01 至 2028-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10714085
• 关键词: Cell Communication; Cell physiology; Cells; Cellular biology; Communication; Communities; Data; Development; Disease; Fibroblasts; Fibrosis; Goals; Growth Factor; Homeostasis; Image; Immune; Immune response; Immunology; Immunology procedure; Inflammation; Inflammatory; Inflammatory Bowel Diseases; Inflammatory Response; Knowledge; Label; Macrophage; Malignant Neoplasms; Methods; Molecular; Nature; Paracrine Communication; Population; Process; Publishing; Reagent; Research; Stromal Cells; System; Technology; Tissues; Vision; base; cell type; chemical genetics; genetic approach; human disease; immune function; innovation; programs; receptor; reconstitution; response; self assembly; therapeutic target; tool; transcriptomic profiling

SUMMARY In tissues, immune cells are well-organized spatially and perform specific functions to dictate tissue homeostasis and inflammation. Yet, it is rarely understood how the organization and functions of immune cells are regulated by their surrounding tissue stroma. The overall vision of the lab is to elucidate the impacts and mechanisms of the interactions between immune and non-immune cell types, in order to understand general principles of how immune functions are regulated within tissues. This may ultimately lead us to program immune responses to restore tissue homeostasis from disease. The lab has discovered that macrophages and fibroblasts, two cell types that are commonly present in mammalian tissues, self-assemble into a tissue-like system that maintains a stable and robust population composition. These homeostatic features rely on paracrine communication of growth factors and direct contact between these cells. This macrophage-fibroblast system provides a unique, accessible and modular platform to discover immune functions in the cellular context of stromal cells and to dissect the underlying mechanisms. Our published and preliminary data formulate the overall hypothesis of the lab: distinct cellular responses emerge from the interactions between macrophages and fibroblasts. The goal of the lab in the next five years is to identify the cellular and molecular bases of the interactions between macrophages and fibroblasts and to characterize how these interactions regulate immune responses during tissue homeostasis or inflammation. We aim to elucidate general principles that regulate functions and organization of immune cells in tissues, by developing new methods to study their interactions and interactive partners, discovering interaction receptors to perturb them, and defining cellular functions dependent on such interactions. To reach this goal, 3 directions will be pursued in my lab: 1) develop fucosyl-labeling, a new cell- based chemical genetic approach, to identify cell-cell interactions, 2) identify molecules responsible for the physical association between macrophages and fibroblasts, leveraging candidate-based genetic approaches, 3) determine how the interactions between macrophages and fibroblasts impact their cellular responses under inflammatory conditions using transcriptome profiling, imaging and immunological assays. Research proposed in this application is innovative because it presents a comprehensive strategy to directly tackle the mechanistic nature of immune-stromal interactions, combined with exploration of a new research paradigm and the development of cutting-edge technologies that will have a fundamental impact in basic cell biology and immunology. The proposed research is significant because it will identify the cellular mechanisms that regulate immune functions critical for maintaining tissue homeostasis and regulating inflammatory responses. My lab will advance our knowledge of inter-cellular processes that may lead to inflammatory disorders and define new possible therapeutic targets. The reagents, tools and experimental systems developed here will benefit the broad scientific community to explore multi-cellular interactions.

概括 在组织中，免疫细胞在空间上井井有条，并执行特定的功能来决定组织稳态 和炎症。然而，很少了解如何调节免疫细胞的组织和功能 通过其周围的组织基质。实验室的总体视野是阐明 免疫和非免疫细胞类型之间的相互作用，以了解如何 免疫功能在组织中受到调节。这最终可能会导致我们对免疫反应进行编程 从疾病中恢复组织稳态。该实验室发现巨噬细胞和成纤维细胞，两个细胞 通常存在于哺乳动物组织中的类型 稳定且强大的人口组成。这些稳态特征依赖于旁分泌的交流 这些细胞之间的生长因子和直接接触。这种巨噬细胞纤维细胞系统提供了独特的， 可访问且模块化平台，以发现基于基础细胞的细胞环境中的免疫功能和 剖析潜在的机制。我们发布的初步数据制定了整体假设 实验室：巨噬细胞与成纤维细胞之间的相互作用出现了不同的细胞反应。 实验室在未来五年中的目标是确定相互作用的细胞和分子碱基 巨噬细胞和成纤维细胞，并表征这些相互作用如何调节免疫反应 组织稳态或炎症。我们旨在阐明规范功能和 通过开发新方法来研究其相互作用和互动 伴侣，发现相互作用受体以扰动它们，并定义基于此类的细胞功能 互动。为了实现这一目标，将在我的实验室中追踪3个方向：1）开发葡萄糖基标记，这是一种新的细胞 - 基于化学遗传方法，以鉴定细胞 - 细胞相互作用，2）确定负责该的分子 巨噬细胞与成纤维细胞之间的物理关联，利用基于候选的遗传方法，3） 确定巨噬细胞和成纤维细胞之间的相互作用如何影响其细胞反应 使用转录组分析，成像和免疫学分析的炎症条件。研究提出 在此应用中，它具有创新性，因为它提出了一种全面的策略，可以直接解决机理 免疫质体相互作用的性质，再加上新的研究范式的探索和 开发尖端技术，将对基本细胞生物学产生根本影响和 免疫学。 拟议的研究很重要，因为它将确定调节的细胞机制 免疫功能对于维持组织稳态和调节炎症反应至关重要。我的实验室 提高我们对可能导致炎症性疾病并定义新的细胞间过程的了解 可能的治疗靶标。这里开发的试剂，工具和实验系统将使广泛 探索多细胞相互作用的科学界。