EGFR Signaling in Macrophages: A Novel Regulator of Immune Responses to H. pylori

巨噬细胞中的 EGFR 信号转导：幽门螺杆菌免疫反应的新型调节剂

• 批准号: 8981548
• 负责人: Dana M. Hardbower
• 金额: $ 2.76万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-06-09 至 2017-06-08
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8981548
• 关键词: Acute; Adenocarcinoma; Antibiotic Therapy; Apoptosis; Bacteria; Cancer Etiology; Cell Line; Cells; Cessation of life; Chronic; Chronic Gastritis; Clinical; Colombia; DNA Damage; Data; Development; Disease; Down-Regulation; Epidermal Growth Factor; Epidermal Growth Factor Receptor; Epithelial Cells; Event; Fellowship; Gastritis; Genes; Goals; Helicobacter Infections; Helicobacter pylori; Heparin Binding; Honduras; Human; Immune; Immune Tolerance; Immune response; Immune system; Immunofluorescence Immunologic; In Vitro; Infection; Inflammation; Inflammatory; Inflammatory Response; Integration Host Factors; Interleukin-10; Interleukins; Knock-out; Knockout Mice; Libraries; Ligands; Link; Luciferases; Macrophage Activation; Mediating; Mediator of activation protein; Modeling; Mus; Myelogenous; Nitric Oxide; Oxidative Stress; Pathogenesis; Pathway interactions; Phagocytosis; Phosphorylation; Play; Population; Production; Proteins; Public Health; Pylorus; Receptor Activation; Receptor Signaling; Regulation; Reporter; Research; Role; Signal Pathway; Signal Transduction; Stomach; T cell response; T-Cell Activation; T-Lymphocyte; Therapeutic Intervention; Time; Tissue Sample; Training; Transactivation; Tumor Necrosis Factor-alpha; Virulence Factors; Western Blotting; Wound Healing; antimicrobial; cancer risk; carcinogenesis; chemical genetics; chemokine; cohort; cytokine; human NOS2A protein; human disease; in vivo; insight; killings; macrophage; malignant stomach neoplasm; microbial; microbicide; mouse model; mutant; new therapeutic target; novel; pathogen; public health relevance; response; targeted treatment; tumorigenesis

 DESCRIPTION (provided by applicant): Helicobacter pylori remains a major public health threat, as half of the world's population is infected. Infection with the pathogen is the primary rsk factor for developing gastric cancer, the third leading cause of cancer death worldwide. Macrophages elicit a highly inflammatory, yet futile immune response to H. pylori, and thereby contribute directly to gastric carcinogenesis. I have determined that macrophages can utilize epidermal growth factor receptor (EGFR) signaling, a well-studied pathway in epithelial cells, but previously unsuspected to be of significance in macrophages. My preliminary data indicate that H. pylori infection is sufficient to induce EGFR phosphorylation and that EGFR signaling plays a major and global role in macrophage activation, polarization and function, all of which are crucial steps in the response to a pathogen. Inhibition of EGFR transactivation results in the downregulation of several key genes, including interleukin (IL)-1ß, tumor necrosis factor (TNF)-a and IL-10. Moreover, inhibiting pEGFR significantly impairs the ability of macrophages to produce nitric oxide, a potent antimicrobial molecule. I will determine the mechanism by which H. pylori induces EGFR signaling in macrophages. Additionally, I will elucidate the downstream targets of EGFR signaling and the effects that inhibition of EGFR activation has on a wide variety of macrophage functions, including polarization, cytokine/chemokine production, phagocytosis, antimicrobial effector production and interactions with T-cells. Using a mouse model with myeloid-specific knockout of EGFR, I will investigate the in vivo effects of EGFR signaling on H. pylori immunopathogenesis. Additionally, I will utilize tissue samples from human cohorts in Colombia and Honduras to assess the involvement of EGFR signaling in macrophages in human disease. The proposed studies will provide fundamental insights into intracellular macrophage signaling and a better understanding of H. pylori pathogenesis. My findings in macrophages in the H. pylori model are potentially applicable to general macrophage function in response to a wide variety of pathogens, opening a new direction of research within the macrophage field. Furthermore, this proposal seeks to ascertain the efficacy of targeting macrophage EGFR signaling for therapeutic intervention in inflammation-driven diseases and in gastric cancer development. This project will be an ideal training vehicle for my plan of continuing in the field of host-pathogen interactions in an academic postdoctoral fellowship. Hypothesis: EGFR activation and signaling has a novel and previously unsuspected role in regulating macrophage activation and function in response to H. pylori. Aim 1: Define the mechanism by which H. pylori infection induces EGFR transactivation. Aim 2: Determine the role of EGFR signaling in macrophage activation, polarization and function. Aim 3: Determine the function of EGFR signaling in macrophages on H. pylori pathogenesis in vivo.

 描述（由申请人提供）：幽门螺杆菌仍然是一个主要的公共卫生威胁，因为世界上一半的人口受到感染。病原体感染是胃癌发生的主要风险因素，胃癌是全球癌症死亡的第三大原因。巨噬细胞引起高度炎症，但对H无效的免疫反应。幽门螺杆菌，从而直接导致胃癌发生。我已经确定巨噬细胞可以利用表皮生长因子受体（EGFR）信号传导，这是一种在上皮细胞中得到充分研究的途径，但以前未被怀疑在巨噬细胞中具有重要意义。我的初步数据表明，H。pylori感染足以诱导EGFR磷酸化，EGFR信号传导在巨噬细胞活化、极化和功能中起主要和全面的作用，所有这些都是至关重要的 对病原体的反应EGFR反式激活的抑制导致几个关键基因的下调，包括白细胞介素（IL）-1 β、肿瘤坏死因子（TNF）-α和IL-10。此外，抑制pEGFR显著损害巨噬细胞产生一氧化氮（一种有效的抗微生物分子）的能力。我将确定H. pylori诱导巨噬细胞中的EGFR信号传导。此外，我将阐明EGFR信号传导的下游靶点以及EGFR活化的抑制对各种巨噬细胞功能的影响，包括极化、细胞因子/趋化因子产生、吞噬作用、抗菌效应物产生以及与T细胞的相互作用。使用骨髓特异性敲除EGFR的小鼠模型，我将研究EGFR信号传导对H。pylori免疫发病机制此外，我将利用来自哥伦比亚和洪都拉斯的人类队列的组织样本来评估EGFR信号在人类疾病中巨噬细胞中的参与。这些研究将为深入了解细胞内巨噬细胞信号传导和更好地理解H。pylori发病机制我在H. pylori模型可应用于一般巨噬细胞对多种病原体的反应，为巨噬细胞领域的研究开辟了新的方向。此外，该提案旨在确定靶向巨噬细胞EGFR信号传导用于炎症驱动的疾病和胃癌发展中的治疗干预的功效。这个项目将是一个理想的培训工具，我的计划继续在该领域的宿主-病原体相互作用的学术博士后奖学金。假设：EGFR激活和信号传导在调节巨噬细胞对H.幽门。目的1：明确H. pylori感染诱导EGFR反式激活。目的2：确定EGFR信号在巨噬细胞活化、极化和功能中的作用。目的3：探讨巨噬细胞EGFR信号通路在H. pylori的体内发病机制。