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.

摘要 在组织中，免疫细胞在空间上组织良好，并执行特定的功能来决定组织的动态平衡 和炎症。然而，人们很少了解免疫细胞的组织和功能是如何调节的 通过它们周围的组织基质。该实验室的总体愿景是阐明 免疫和非免疫细胞类型之间的相互作用，以了解如何 免疫功能在组织内受到调节。这可能最终导致我们编程免疫反应 从疾病中恢复组织动态平衡。实验室发现，巨噬细胞和成纤维细胞是两种细胞 在哺乳动物组织中普遍存在的类型，自组装成一个类似组织的系统，维持一个 人口构成稳定稳健。这些动态平衡的特征依赖于旁分泌通讯 生长因子和这些细胞之间的直接接触。这种巨噬细胞-成纤维细胞系统提供了一种独特的、 可访问的模块化平台，可在基质细胞的细胞环境中发现免疫功能，并 剖析潜在的机制。我们已发表的和初步的数据阐明了 实验室：巨噬细胞和成纤维细胞之间的相互作用产生了不同的细胞反应。 该实验室在未来五年的目标是确定相互作用的细胞和分子基础 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在 组织动态平衡或炎症。我们的目标是阐明调节功能和 通过开发研究免疫细胞相互作用和相互作用的新方法，在组织中组织免疫细胞 合作伙伴，发现相互作用的受体来扰乱他们，并定义依赖于此的细胞功能 互动。为了实现这一目标，我的实验室将朝着三个方向努力：1)开发岩藻糖基标记，一种新的细胞- 基于化学遗传学的方法，以确定细胞-细胞相互作用，2)确定负责 巨噬细胞和成纤维细胞之间的物理联系，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它们的细胞反应 使用转录组图谱、成像和免疫学分析的炎症情况。建议进行的研究 在这一应用中具有创新性，因为它提出了一种全面的策略来直接解决机械 免疫-基质相互作用的性质，结合新研究范式的探索和 尖端技术的发展将对基础细胞生物学和 免疫学。 这项拟议的研究意义重大，因为它将确定调节 对维持组织动态平衡和调节炎症反应至关重要的免疫功能。我的实验室会 提高我们对可能导致炎症性疾病的细胞间过程的知识，并定义新的 可能的治疗靶点。这里开发的试剂、工具和实验系统将使广大民众受益 科学界探索多细胞相互作用。