Macrophage Reprogramming During Granuloma Formation in the Zebrafish

斑马鱼肉芽肿形成过程中的巨噬细胞重编程

• 批准号: 10546475
• 负责人: David M. Tobin
• 金额: $ 47.66万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-03-03 至 2027-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10546475
• 关键词: Adherens Junction; Affect; Animals; Appearance; Architecture; Bacteria; Biology; Cells; Chimera organism; Communicable Diseases; Containment; Cues; Data; Desmosomes; Development; Disease; Disease Outcome; Disease Progression; E-Cadherin; Epithelium; Event; Focal Adhesion Kinase 1; Genetic; Granuloma; Growth; Human; Image; Immune; Immune response; Immune signaling; Immune system; Individual; Infection; Inflammatory; Interleukin-13; Interleukin-4; Larva; Lead; Macrophage; Maintenance; Malignant Neoplasms; Marrow; Mediating; Mesenchymal; Modeling; Morphology; Mus; Mycobacterium Infections; Necrosis; Neoplasm Metastasis; Optics; Outcome; Pathway interactions; Phenotype; Play; Process; Reporter Genes; Resolution; Role; STAT6 gene; Signal Induction; Signal Pathway; Signal Transduction; Source; Stimulus; Structure; Techniques; Testing; Tight Junctions; Transgenic Organisms; Tuberculosis; Zebrafish; cell motility; combat; design; epithelial to mesenchymal transition; experimental study; human disease; mutant; mycobacterial; nonhuman primate; notch protein; novel therapeutic intervention; overexpression; pharmacologic; programs; response; single-cell RNA sequencing; tool

Abstract Granulomas form as a conserved host response to a variety of inflammatory and infectious stimuli. As granulomas assemble, macrophages interdigitate and undergo a striking morphological transition, taking on an epithelioid appearance. The basis for this transformation and the consequences to disease are not well understood. We identified a conserved reprogramming of macrophages that underlies the assembly and stability of mycobacterial granulomas. Using a zebrafish model, we find that broad epithelial modules and structures are induced during tuberculous granuloma formation and are critical for granuloma integrity. In this project we will 1) assess how specific Type 2 immune signals interact with countervailing Type 1 signals to coordinate epithelioid transformation and granuloma assembly; 2) test the role of the EMP2/Focal Adhesion Kinase (FAK) pathway in granuloma stability, disaggregation and the dissemination of infection; 3) based on scRNA-seq analysis of granulomas as well as macrophages isolated from individual animals, assess the role of JAG1-Notch in granuloma formation, maintenance, and infection trajectory. We will extend findings from these studies into analysis of human disease. Overall, this proposal will test the hypothesis that, in a striking parallel to mesenchymal-to-epithelial transitions in development and cancer, macrophages draw on classical developmental signaling pathways to undergo an epithelial-like transition. This reprogramming underlies the central structure of tuberculosis and defines interactions with the host immune system. We will test how perturbations of these pathways lead to alterations in disease progression and outcome. A new perspective on this critical structure may have important implications for our understanding of disease progression and provides opportunities for new therapeutic approaches.

摘要 肉芽肿是宿主对多种炎症和感染性刺激的保守反应。作为 肉芽肿聚集，巨噬细胞相互交错，并经历了惊人的形态学转变，呈现出一种 上皮样外观。这种转变的基础和对疾病的后果并不好 明白我们确定了一种保守的巨噬细胞重编程，它是组装的基础， 分枝杆菌肉芽肿的稳定性。使用斑马鱼模型，我们发现广泛的上皮模块和 结构在结核性肉芽肿形成期间被诱导并且对于肉芽肿的完整性是关键的。在这 我们将1）评估特定的2型免疫信号如何与抵消的1型信号相互作用， 协调上皮样转化和肉芽肿组装; 2）测试EMP 2/局灶性粘附的作用， 激酶（FAK）通路在肉芽肿稳定、解聚和感染播散中的作用; 3）基于 对从个体动物分离的肉芽肿以及巨噬细胞进行scRNA-seq分析，评估其作用 JAG 1-Notch在肉芽肿形成、维持和感染轨迹中的作用。我们将把调查结果从 将这些研究转化为人类疾病的分析。总的来说，这项建议将测试的假设，在一个惊人的 与发育和癌症中的间充质-上皮转化平行，巨噬细胞利用经典的 发育信号通路经历上皮样转变。这种重新编程是 结核病的中心结构，并确定与宿主免疫系统的相互作用。我们将测试如何 这些途径的干扰导致疾病进展和结果的改变。的新视角 这一关键结构可能对我们理解疾病进展具有重要意义， 为新的治疗方法提供了机会。