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（由应用程序提供）：幽门螺杆菌仍然是主要的公共卫生威胁，因为世界一半的人口被感染。病原体感染是胃癌发展的主要RSK因子，这是全球癌症死亡的第三主要原因。巨噬细胞引起对幽门螺杆菌的高度炎症，但徒劳的免疫反应，从而直接促进胃癌发生。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，这是上皮细胞中良好的途径，但以前未经证实在巨噬细胞中具有重要意义。我的初步数据表明幽门螺杆菌感染足以诱导EGFR磷酸化，而EGFR信号在巨噬细胞激活，极化和功能中起着重要而全球的作用，所有这些都至关重要，所有这些都是至关重要的 对病原体的反应的步骤。 EGFR反式激活的抑制导致几个关键基因的下调，包括白介素（IL）-1ß，肿瘤坏死因子（TNF）-A和IL-10。此外，抑制PEGFR会显着损害巨噬细胞产生一氧化氮的能力，即一种潜在的抗菌分子。我将确定幽门螺杆菌在巨噬细胞中诱导EGFR信号传导的机制。此外，我将阐明EGFR信号传导的下游靶标，以及抑制EGFR激活对多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，吞噬细胞增多，抗菌素效应的产生和与T细胞的相互作用。使用具有EGFR的粒细胞特异性敲除的小鼠模型，我将研究EGFR信号传导对幽门螺杆菌免疫发病发生的体内影响。此外，我将利用哥伦比亚和洪都拉斯人类人群中的组织样本评估EGFR信号传导参与巨噬细胞中人类疾病中的涉及。拟议的研究将提供对细胞内巨噬细胞信号传导的基本见解，并更好地了解幽门螺杆菌发病机理。我在幽门螺杆菌模型中巨噬细胞中的发现可能适用于多种病原体的一般巨噬细胞功能，在巨噬细胞领域开辟了新的研究方向。此外，该提案旨在确定靶向巨噬细胞EGFR信号传导在炎症驱动疾病和胃癌发展中的治疗干预的有效性。该项目将是我在学术博士后奖学金中继续在主管疾病互动领域继续进行的理想训练工具。假设：EGFR激活和信号传导在确定幽门螺杆菌的巨噬细胞激活和功能方面具有新颖且先前未刺的作用。目标1：定义幽门螺杆菌感染诱导EGFR反式激活的机制。 AIM 2：确定EGFR信号在巨噬细胞激活，极化和功能中的作用。 AIM 3：确定EGFR信号在巨噬细胞中幽门螺杆菌发病机理中的功能。