Deciphering macrophage versus neutrophil signaling and effector functions in immune responses in vivo

解读体内免疫反应中巨噬细胞与中性粒细胞信号传导和效应器功能

• 批准号: 10501204
• 负责人: Emily Rosowski
• 金额: $ 33.55万
• 依托单位: CLEMSON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-15 至 2027-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10501204
• 关键词: Aspergillus fumigatus; Biological Process; C Type Lectin Receptors; Cell Death; Cell physiology; Cells; Chemicals; Complex; Disease; Experimental Models; Future; Genes; Genetic; Goals; Homeostasis; Immune; Immune response; Immunosuppressive Agents; Inflammation; Inflammatory; Inflammatory Response; Innate Immune Response; Laboratories; Modeling; Opportunistic Infections; Organ; Pathway interactions; Precision therapeutics; Predisposition; Research; Role; Signal Pathway; Signal Transduction; Sterility; System; Tissues; Toll-like receptors; Zebrafish; autoinflammatory; cell type; common treatment; human disease; in vivo; inhibitor; macrophage; neutrophil; pathogen; pathogenic fungus; programs; receptor; response; side effect; tool

Project Summary/Abstract Immune responses are the result of a combined effort of multiple cell types. In innate immune responses the activity of both macrophages and neutrophils is important in targeting pathogens, resolving tissue damage, and maintaining homeostasis. My laboratory uses the larval zebrafish model to determine the differential role and functions of these two innate cell types in inflammatory responses. The overarching goal of my research program is to identify specific signaling pathways, including signals, receptors, and effector mechanisms, that are required for the function of macrophages versus neutrophils. During human disease, the function of just a subset of these cells may go awry, yet common treatments target broad pathways that inhibit multiple cell types and therefore cause harmful side effects. Identification of discrete mechanisms used by single cell types in inflammatory disease will provide targets for future precision therapies. We have developed an experimental system in larval zebrafish using the fungal pathogen A. fumigatus that separates the function of macrophages and neutrophils. Over the next five years, we propose to combine this system with genetic targeting tools and chemical inhibitors to interrogate the requirement of intracellular killing mechanisms, cell death pathways, Toll-like receptors, and C-type lectin receptors in macrophage versus neutrophil functions against A. fumigatus and in response to PAMPs and DAMPs. In future research, we will expand our experimental model to interrogate the role of these genes and pathways in other inflammatory scenarios, such as sterile inflammation during auto-inflammatory disease. Altogether, this research will delineate complete pathways differentially required for innate immune cell function.

项目总结/摘要 免疫反应是多种细胞类型共同作用的结果。在先天免疫反应中， 巨噬细胞和嗜中性粒细胞的活性在靶向病原体、解决组织损伤和 维持体内平衡我的实验室使用斑马鱼幼体模型来确定差异作用， 这两种先天细胞类型在炎症反应中的功能。我研究的首要目标是 该计划旨在确定特定的信号传导途径，包括信号，受体和效应器 机制，这是所需的巨噬细胞与中性粒细胞的功能。在人 疾病，只是这些细胞的一个子集的功能可能会出错，但常见的治疗目标广泛 抑制多种细胞类型并因此导致有害副作用的途径。离散识别 单细胞类型在炎症性疾病中使用的机制将为未来的精确度提供目标 治疗我们已经开发了一个实验系统，在斑马鱼幼虫使用真菌病原体A。 分离巨噬细胞和中性粒细胞功能的烟曲霉菌。在未来五年，我们建议 联合收割机将该系统与遗传靶向工具和化学抑制剂相结合， 细胞内杀伤机制、细胞死亡途径、Toll样受体和C型凝集素受体， 巨噬细胞与嗜中性粒细胞功能对A.烟曲霉和响应PAMP和DAMP。今后 研究，我们将扩大我们的实验模型，以询问这些基因和途径在其他疾病中的作用。 炎症情况，例如自身炎症疾病期间的无菌炎症。总之，这 研究将描绘出先天免疫细胞功能所需的不同的完整途径。