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，免疫细胞在空间上组织良好，并执行特定功能来决定组织稳态 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。实验室的总体愿景是阐明影响和机制 免疫和非免疫细胞类型之间的相互作用，以了解如何相互作用的一般原理 免疫功能在组织内受到调节。这可能最终导致我们对免疫反应进行编程 恢复疾病中的组织稳态。实验室发现巨噬细胞和成纤维细胞这两种细胞 通常存在于哺乳动物组织中的类型，自组装成一个类似组织的系统，该系统维持 人口结构稳定、强劲。这些稳态功能依赖于旁分泌通讯 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独特的、 可访问的模块化平台，用于发现基质细胞细胞环境中的免疫功能并 剖析底层机制。我们发表的初步数据提出了总体假设 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。 该实验室未来五年的目标是确定细胞和分子之间相互作用的基础 巨噬细胞和成纤维细胞，并描述这些相互作用如何调节免疫反应 组织稳态或炎症。我们的目标是阐明调节功能和功能的一般原则 通过开发新方法来研究组织中免疫细胞的相互作用和相互作用 合作伙伴，发现干扰它们的相互作用受体，并定义依赖于这种受体的细胞功能 互动。为了实现这一目标，我的实验室将追求 3 个方向：1）开发岩藻糖基标记，一种新的细胞- 基于化学遗传方法，识别细胞间相互作用，2）识别负责 巨噬细胞和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它们的细胞反应 使用转录组分析、成像和免疫学测定来确定炎症状况。研究建议 该应用程序具有创新性，因为它提出了直接解决机械问题的综合策略 免疫基质相互作用的本质，结合对新研究范式的探索和 开发将对基础细胞生物学产生根本性影响的尖端技术 免疫学。 拟议的研究意义重大，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。我的实验室将 增进我们对可能导致炎症性疾病的细胞间过程的了解，并定义新的 可能的治疗目标。这里开发的试剂、工具和实验系统将惠及广大 科学界致力于探索多细胞相互作用。