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

项目摘要 特发性肺纤维化(IPF)是一种以胶原沉积进展为特征的疾病 肺和最终的肺功能丧失。IPF是致命的，治疗这种疾病的方法有限，缺乏疗效。 与IPF相关的大部分死亡可归因于急性加重(AE)或迅速恶化 在肺功能方面，通常会导致在确诊后几个月内死亡。然而，过去十年中的研究 也认识到肺内细菌在加剧IPF病程中的作用。一项研究发现 在住院的IPF患者中，呼吸道感染是类似死亡率的原因 与AE相比。其他研究已经确认了细菌属葡萄球菌的存在和 肺内的链球菌与IPF患者预后不良有关。我们的实验室有初步数据 表明博莱霉素诱导的纤维化肺损伤小鼠随后感染了 与纤维化的小鼠相比，金黄色葡萄球菌或肺炎链球菌的存活率降低。 只有肺损伤。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，在这项建议中，我们试图确定纤维化对免疫的影响。 对细菌感染的反应。我们已经鉴定了胶原受体盘状结构域受体2(DDR2)是 纤维化肺损伤后免疫细胞功能的可能介体。我们已经确定DDR2是 肝纤维化小鼠巨噬细胞和DDR2-/-骨髓源性巨噬细胞表达下调 显示细菌吞噬和中性粒细胞趋化因子产生水平降低，这两个关键功能在 清除细菌感染。这项提议将检验纤维化肺损伤损害的假设 通过下调DDR2进行抗菌宿主防御。这一假设将通过两个具体的 目的：1)确定胶原受体DDR2在调节巨噬细胞抗菌反应中的作用 和2)DDR2在调节中性粒细胞募集减少中的作用 纤维化后细菌性肺炎。这些目的的实验将通过使用基因来完成 工程化小鼠模型，从这些小鼠衍生的细胞，以及研究DDR2在不同类型的 免疫细胞的功能。这些创新研究的结果可能会为帮助改善IPF的治疗提供参考 呼吸道感染后的患者结局。完成这项提案还将允许申请人 接受实验设计、实施和解释方面的严格培训，这将帮助她成为 成功的、独立的科学家。

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.