Pathogenic monocyte response to chronic lung inflammation in cystic fibrosis

致病性单核细胞对囊性纤维化慢性肺部炎症的反应

基本信息

批准号：
10545042
负责人：
Emanuela Marina Bruscia
金额：
$ 77.17万
依托单位：
YALE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-01-01 至 2025-11-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10545042
关键词：
Affect Bacteria Bacterial Infections Blood Cells Bone Marrow CD34 gene Cell Separation Cells Chronic Cicatrix Cystic Fibrosis Cystic Fibrosis Transmembrane Conductance Regulator Data Delta F508 mutation Deterioration Development Disease Epigenetic Process Exposure to Feedback Functional disorder Gene Expression Profile Genes Goals Hematopoietic stem cells Host Defense Human Immune Immunity Immunologic Memory Immunology Impairment Individual Infection Inflammation Inflammatory Inflammatory Response Investigation Knockout Mice Life Expectancy Lipopolysaccharides Lung Lung immune response Lung infections Macrophage Mediating Methodology Modeling Mus Myelogenous Pathogenesis Pathogenicity Pathologic Pathway interactions Pseudomonas aeruginosa Publishing Pulmonary Cystic Fibrosis Pulmonary Inflammation Pulmonary Pathology Recovery Research Research Personnel Respiratory Failure Signal Transduction Structure of parenchyma of lung Technology Testing Therapeutic Intervention Time Tissues Training Transforming Growth Factor beta Translating Umbilical Cord Blood Transplantation Work Xenograft Model chronic inflammatory disease cystic fibrosis mouse cystic fibrosis patients drug efficacy fighting hematopoietic stem cell differentiation immunodeficient mouse model improved innovation lung injury memory acquisition migration monocyte mouse model novel pharmacologic prevent progenitor pulmonary function recruit response stem cells therapeutic target therapeutically effective

项目摘要

PROJECT SUMMARY Researchers still do not understand the mechanisms behind the progressive and irreversible lung structural damage that ultimately causes respiratory failure in patients with cystic fibrosis (CF). We have developed a CF mouse model of chronic inflammation that recapitulates the progressive and irreversible lung tissue remodeling in late-stage CF lung disease. The overall goal here is to understand the cellular mechanisms that lead to progressive and irreversible CF lung deterioration. The objective is to study how inflammatory monocytes and monocyte-derived MΦs (MΦs) contribute to the development of irreversible lung tissue remodeling in CF. Our central hypothesis is that, in CF, chronic lung exposure to lipopolysaccharide (LPS) increases recruitment of inflammatory monocytes to the lungs and that these monocytes are programmed to cause tissue damage while failing to effectively fight the infection. Moreover, we hypothesize that this is initiated by the loss of CFTR function in hematopoietic stem/progenitor cells in the bone marrow. The rationale is based on observations that an increased number of inflammatory monocytes and monocyte-derived MΦs are found in the lungs of patients with CF. This feature is recapitulated by our CF mouse model when chronically exposed to LPS. Moreover, after six weeks of recovery from chronic LPS exposure, monocytes from CF lungs maintain a “pro-inflammatory” signature, suggesting a permanent change in CF monocyte functions. Furthermore, we conducted studies using a mouse model in which migration of inflammatory monocytes is impaired (Ccr2-/- mice). These studies suggest that the inflammatory monocytes drive the lung tissue remodeling caused by chronic exposure to LPS. Our specific aims will test the following hypotheses: (aim 1) that lowering the recruitment of circulating inflammatory monocytes to CF lungs during chronic exposure to LPS is sufficient to reduce TGFβ signaling and mitigate tissue remodeling in CF lungs without compromising host defense against bacteria; (aim 2) that the innate immune memory acquisition in CF myeloid progenitor stem cells, caused by chronic LPS exposure, will generate inflammatory monocytes that fail to effectively clear infections and that cause profound lung tissue damage; (aim 3) that cell-autonomous CFTR dysfunction in hematopoietic stem/progenitor cells and monocytes contributes to pathogenic responses to chronic lung exposure to LPS. The contribution is significant because it will result in a better understanding of the pathogenesis of immune-mediated diseases in CF and in other chronic inflammatory diseases with persistent bacterial lung infections. Our proposed research is innovative because we will use novel mouse models, we will bridge together methodologies in lung immunology and hematopoietic stem cell fields, and we will use unbiased cutting-edge technologies. At the completion of this work, we will have identified novel mechanisms by which chronic instigation of the lung immune response in CF disrupts the monocytic-lung axis feedback, leading to progressive lung damage. Ultimately, these studies may identify new pathways for effective therapeutic interventions in slowing down CF lung deterioration.

项目概要研究人员仍然不了解进行性和不可逆的肺结构性病变背后的机制我们开发了一种最终导致囊性纤维化 (CF) 患者呼吸衰竭的 CF。慢性炎症小鼠模型，再现进行性和不可逆的肺组织重塑晚期 CF 肺病的总体目标是了解导致 CF 肺病的细胞机制。进行性和不可逆的 CF 肺部恶化的目的是研究炎症单核细胞和单核细胞衍生的 MΦs (MΦs) 有助于 CF 中不可逆肺组织重塑的发展。中心假设是，在 CF 中，长期肺部暴露于脂多糖 (LPS) 会增加炎症单核细胞进入肺部，这些单核细胞被编程为引起组织损伤，同时此外，我们认为这是由于 CFTR 功能丧失所致。其基本原理是基于以下观察：在患有以下疾病的患者肺部发现炎性单核细胞和单核细胞衍生的 MΦ 数量增加 CF.我们的 CF 小鼠模型在长期暴露于 LPS 后，也重现了这一特征。从慢性 LPS 暴露中恢复数周后，CF 肺部的单核细胞仍保持“促炎”状态签名，表明 CF 单核细胞功能发生永久性变化此外，我们使用其进行了研究。这些研究表明，炎症单核细胞迁移受损的小鼠模型（Ccr2-/- 小鼠）。炎症单核细胞驱动长期暴露于 LPS 引起的肺组织重塑。具体目标将检验以下假设：（目标 1）降低循环炎症的募集慢性暴露于 LPS 期间单核细胞进入 CF 肺部足以减少 TGFβ 信号传导并减轻组织在不损害宿主对细菌的防御能力的情况下重塑 CF 肺部（目标 2）由慢性 LPS 暴露引起的 CF 骨髓祖干细胞的记忆获取将产生炎症单核细胞无法有效清除感染并导致严重的肺组织损伤； 3）造血干细胞/祖细胞和单核细胞中的细胞自主CFTR功能障碍导致肺部长期暴露于脂多糖的致病反应的贡献是显着的，因为它会导致更好地了解 CF 和其他慢性炎症中免疫介导疾病的发病机制我们提出的研究具有创新性，因为我们将使用新型药物。小鼠模型，我们将把肺免疫学和造血干细胞领域的方法结合起来，在这项工作完成后，我们将使用公正的尖端技术。 CF 中肺部免疫反应的慢性刺激破坏单核细胞肺轴的机制最终，这些研究可能会找到有效的新途径。减缓 CF 肺部恶化的治疗干预措施。