Dissecting the Role of DDR2 in the Modulation of Antibacterial Host Defense Post Fibrotic Lung Injury

剖析 DDR2 在调节纤维化肺损伤后抗菌宿主防御中的作用

• 批准号: 10360419
• 负责人: Helen Ivory Warheit-Niemi
• 金额: $ 3.78万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-05-01 至 2023-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10360419
• 关键词: Acute; Affect; Anti-Bacterial Agents; Antibacterial Response; Bacteria; Bacterial Infections; Bacterial Pneumonia; Biological; Biological Assay; Biological Response Modifiers; Bleomycin; Bone Marrow; CXCL1 gene; CXCL2 gene; Cell physiology; Cells; Cessation of life; Chemotaxis; Cicatrix; Clinical; Collagen; Collagen Receptors; Data; Defect; Deposition; Deterioration; Development; Diagnosis; Disease; Down-Regulation; Epigenetic Process; Exhibits; Experimental Designs; Fibrosis; Gene Expression; Genetic Transcription; Genetically Engineered Mouse; Genus staphylococcus; Goals; Health; Host Defense; Human; Immune; Immune response; Immunomodulators; Impairment; In Vitro; Infection; Innate Immune System; Interstitial Lung Diseases; Knowledge; Lead; Lung; Lung infections; Lysosomes; Measures; Mediating; Migration Assay; Modification; Molecular; Mus; Neutrophil Infiltration; Nitric Oxide; Outcome; Output; Oxygen; Patient-Focused Outcomes; Patients; Phagocytes; Phagocytosis; Phagosomes; Predisposition; Production; Pulmonary Fibrosis; Reactive Oxygen Species; Regulation; Respiratory Failure; Respiratory Tract Infections; Role; Scientist; Sepharose; Staphylococcal Pneumonia; Staphylococcus aureus infection; Streptococcus; Streptococcus pneumoniae; Survival Rate; Testing; Time; Tissues; Training; chemokine; chromatin immunoprecipitation; differential expression; discoidin domain receptor 2; experimental study; idiopathic pulmonary fibrosis; immunoregulation; improved; in vitro Assay; in vivo; innovation; insight; lung injury; macrophage; methicillin resistant Staphylococcus aureus; migration; mortality; neutrophil; pathogenic bacteria; patient population; prevent; pulmonary function; recruit; response; transcriptome sequencing

Project Abstract Idiopathic pulmonary fibrosis (IPF) is a disease characterized by the progression of collagen deposition in the lung and eventual loss of lung function. IPF is fatal and treatments for the disease are limited and lacking efficacy. Much of the mortality associated with IPF can be attributed to acute exacerbation (AE), or a rapid deterioration in lung function, often leading to death within a few months of diagnosis. However, studies within the last decade have also recognized a role for bacteria within the lung in exacerbating IPF disease course. One study found that respiratory infections were the cause of similar mortality rates in hospitalized IPF patient populations compared to AE. Other studies have identified the presence of bacterial genera Staphylococcus and Streptococcus within the lung as being associated with poor IPF patient outcomes. Our lab has preliminary data indicating that mice with bleomycin-induced fibrotic lung injury that were subsequently infected with Staphylococcus aureus or Streptococcus pneumoniae had decreased survival compared to mice with fibrotic lung injury alone. We have also determined that fibrotic mice have impaired ability to clear a bacterial infection compared to non-fibrotic mice. Therefore, in this proposal, we seek to identify the effect of fibrosis on the immune response to bacterial infection. We have identified the collagen receptor discoidin domain receptor 2 (DDR2) as a possible mediator of immune cell function following fibrotic lung injury. We have determined that DDR2 is downregulated in macrophages isolated from fibrotic mice and that DDR2-/- bone marrow-derived macrophages show decreased levels of bacterial phagocytosis and neutrophil chemokine production, two critical functions in the clearance of bacterial infections. This proposal will test the hypothesis that fibrotic lung injury impairs antibacterial host defense via the downregulation of DDR2. This hypothesis will be tested through two specific aims: 1) determine the role of collagen receptor DDR2 in regulating macrophage antibacterial responses following pulmonary fibrosis and 2) characterize the role of DDR2 in mediating decreased neutrophil recruitment in post-fibrosis bacterial pneumonia. Experiments for these aims will be completed with the use of genetically engineered mouse models, cells derived from such mice, and in vitro assays studying the role of DDR2 in various immune cell functions. The results from these innovative studies may inform treatments that help improve IPF patient outcomes following respiratory infection. Completion of this proposal will also allow for the applicant to receive rigorous training in experimental design, implementation, and interpretation that will help her become a successful, independent scientist.

项目摘要 特发性肺纤维化（IPF）是一种以胶原沉积在肺组织中进展为特征的疾病。 肺并最终丧失肺功能。 IPF 是致命的，并且该疾病的治疗方法有限且缺乏疗效。 与 IPF 相关的大部分死亡可归因于急性加重 (AE)，或病情迅速恶化 肺功能受损，通常导致诊断后几个月内死亡。然而，近十年的研究 还认识到肺部细菌在加剧 IPF 病程中的作用。一项研究发现 呼吸道感染是 IPF 住院患者死亡率相似的原因 与AE相比。其他研究已确定存在葡萄球菌属细菌和 肺部链球菌与 IPF 患者预后不良有关。我们实验室有初步数据 表明患有博来霉素诱导的纤维化肺损伤的小鼠随后被感染 与纤维化小鼠相比，金黄色葡萄球菌或肺炎链球菌的存活率降低 单独肺损伤。我们还确定纤维化小鼠清除细菌感染的能力受损 与非纤维化小鼠相比。因此，在本提案中，我们试图确定纤维化对免疫的影响 对细菌感染的反应。我们已将胶原蛋白受体盘状蛋白结构域受体 2 (DDR2) 鉴定为 纤维化肺损伤后免疫细胞功能的可能介质。我们确定DDR2是 从纤维化小鼠分离的巨噬细胞和 DDR2-/- 骨髓来源的巨噬细胞中下调 显示细菌吞噬作用和中性粒细胞趋化因子产生水平下降，这是细菌吞噬作用和中性粒细胞趋化因子产生的两个关键功能 清除细菌感染。该提案将检验纤维化肺损伤损害的假设 通过下调 DDR2 发挥抗菌宿主防御作用。这个假设将通过两个特定的 目的：1）确定胶原蛋白受体DDR2在调节巨噬细胞抗菌反应中的作用 肺纤维化后 2) 描述 DDR2 在介导中性粒细胞募集减少中的作用 纤维化后细菌性肺炎。这些目标的实验将通过使用遗传技术来完成 工程小鼠模型、源自此类小鼠的细胞以及研究 DDR2 在各种疾病中的作用的体外测定 免疫细胞功能。这些创新研究的结果可能为有助于改善 IPF 的治疗提供信息 呼吸道感染后的患者结果。完成该提案还将使申请人能够 在实验设计、实施和解释方面接受严格的培训，这将帮助她成为一名 成功的、独立的科学家。