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

项目摘要/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 巨噬细胞和中性粒细胞的活性在靶向病原体、解决组织损伤和 维持动态平衡。我的实验室使用斑马鱼幼体模型来确定不同的作用和 这两种先天细胞类型在炎症反应中的作用。我研究的首要目标是 程序是识别特定的信号通路，包括信号、受体和效应器 巨噬细胞与中性粒细胞功能所需的机制。在人类 疾病，这些细胞中的一个子集的功能可能会出错，但常见的治疗方法是广泛的 抑制多种细胞类型从而导致有害副作用的通路。离散性的识别 单细胞类型用于炎症性疾病的机制将为未来的精确度提供靶点 治疗。我们已经开发了一种在斑马鱼幼体上使用真菌病原体A. 分离巨噬细胞和中性粒细胞功能的烟雾剂。在未来五年，我们建议 将该系统与基因靶向工具和化学抑制剂相结合，以询问对 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 巨噬细胞与中性粒细胞对烟曲霉菌的作用以及对PAMPs和潮湿的反应。在未来 研究，我们将扩展我们的实验模型，以询问这些基因和途径在其他 炎症性场景，如自发性炎症性疾病期间无菌炎症。总而言之，这 研究将描绘先天免疫细胞功能不同所需的完整途径。

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.