Alveolar Macrophage Iron Overload in COPD Pathogenesis

肺泡巨噬细胞铁过载在慢性阻塞性肺病发病机制中的作用

• 批准号: 10740293
• 负责人: WILLIAM ZHENGYANG ZHANG
• 金额: $ 16.9万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-01 至 2028-07-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10740293
• 关键词: Acceleration; Address; Advisory Committees; Alveolar; Alveolar Macrophages; Alveolus; Area; Award; Biological; Biological Markers; Biology; Bronchoalveolar Lavage Fluid; Cause of Death; Cell Death; Cells; Chronic Obstructive Pulmonary Disease; Clinical; Clinical Data; Data; Data Set; Defect; Development; Development Plans; Disease; Disease Marker; Disease Outcome; Disease model; Environment; Epithelial Cells; Exhibits; Ferritin; Functional disorder; Gene Expression; Gene Expression Profile; Genes; Genetic; Goals; Histologic; Homeostasis; Human; Immune; Immune response; Immunology; Infection; Inflammation; Inflammatory; Inflammatory Response; Injury; Institution; Iron; Iron Overload; Knowledge; Link; Lipid Peroxidation; Lung; Lung diseases; Macrophage; Measures; Medicine; Mentorship; Modeling; Mus; National Heart, Lung, and Blood Institute; Nuclear Receptor Coactivator 4; Pathogenesis; Pathway interactions; Patients; Phagocytes; Phagocytosis; Phenotype; Physicians; Physiological; Pneumococcal Infections; Positioning Attribute; Production; Proteins; Pulmonary Emphysema; Recombinants; Research; Research Personnel; Resources; Respiratory Disease; Risk Factors; Role; Scientist; Sentinel; Severity of illness; Smoke; Smoker; Smoking; Source; Streptococcus pneumoniae; Structure of parenchyma of lung; Surrogate Markers; Techniques; Testing; Therapeutic; Time; Training; Translational Research; alveolar epithelium; career development; cigarette smoke; cigarette smoke-induced; cigarette smoke-induced lung injury; clinically relevant; cohort; cytokine; experience; experimental study; exposure to cigarette smoke; extracellular; genetic signature; immune activation; improved; innovation; iron metabolism; lung injury; mouse model; novel; pathogen; prospective; pulmonary function; radiological imaging; response; single-cell RNA sequencing; skills; small airways disease; targeted treatment; therapeutic target; therapy development; tissue injury; transcriptome sequencing; uptake

PROJECT SUMMARY Chronic obstructive pulmonary disease (COPD) is a smoking-associated respiratory disease and is the 3rd lead- ing cause of death worldwide. There are increased numbers of dysfunctional airway and alveolar macrophages (AMs) in the lungs of smokers and COPD patients, localizing to areas of injury. Despite this connection, the mechanisms behind how cigarette smoke (CS) elicits AM dysfunction, and how AM dysfunction facilitates the development of small airways disease and emphysema, two defining features of COPD, are poorly understood. This proposal addresses this critical gap in knowledge and tests the hypothesis that AM dysfunction in COPD is mechanistically linked to abnormal iron accumulation in these cells. Using a multicenter prospective COPD (SPIROMICS) cohort, we previously associated increased levels of iron and iron-related proteins in the bron- choalveolar lavage fluid of smokers and COPD patients with adverse clinical COPD outcomes. AMs are the putative source for this lung extracellular iron, as AMs from smokers and COPD patients are iron-overloaded and release iron in culture. We replicated this clinical phenomenon of AM iron accumulation and release using a murine CS-exposure model. We then used single-cell RNA sequencing and discovered novel AM subsets which have a unique iron-related gene expression signature that is consistent with increased iron uptake. These “iron macrophages”, which we designate as FeMacs, have decreased expression of genes associated with phagocytosis and immune activation, suggesting that this CS-induced AM iron accumulation may have functional consequences for AMs, and potentially for the CS-exposed lung. We will test our hypothesis that FeMacs or- chestrate lung injury development in COPD both mechanistically using our murine CS model and translationally using the SPIROMICS cohort. Aim 1 will compare CS-induced small airways damage and emphysema develop- ment between control mice and mice with AMs deficient in nuclear receptor coactivator 4 (Ncoa4ΔCd11c), an iron metabolism defect which mitigates CS-induced iron accumulation. Aim 2 examines Ncoa4ΔCd11c and Ncoa4fl/fl control mice in a CS-Streptococcus pneumoniae infection 2-hit model, thereby determining whether reducing AM iron overload can alleviate CS-induced AM dysfunction and improve response to pathogen. Aim 3 defines the clinical relevance of AM iron accumulation in human COPD and tests AM expression of iron genes and AM iron content as markers of COPD severity. This proposal presents a five-year career development plan that builds on my previous research and integrates the different domains of expertise of my mentorship and advisory teams. It entails a targeted training plan that is tailored towards the development of specific areas related to immunology, macrophage biology, iron biology, and translational research, facilitated by the physical and intel- lectual resources provided by the academic environment at Weill Cornell Medicine. The proposed experiments, didactic training, as well as mentorship team will position me with a unique set of interdisciplinary skills that will enable my transition to independence as a physician-scientist in lung and macrophage biology and iron biology.

项目摘要 慢性阻塞性肺病（COPD）是一种与吸烟相关的呼吸道疾病，是第三大疾病- 死亡原因全世界。功能障碍的气道和肺泡巨噬细胞数量增加 (AMs)在吸烟者和COPD患者的肺中，定位于损伤区域。尽管有这种联系， 香烟烟雾（CS）如何诱发AM功能障碍，以及AM功能障碍如何促进 小气道疾病和肺气肿的发展是COPD的两个定义性特征，但对其了解甚少。 这项提案解决了这一关键的知识差距，并测试了COPD患者AM功能障碍的假设， 与这些细胞中异常的铁积累有关。使用多中心前瞻性COPD （螺旋体学）队列，我们以前与铁和铁相关蛋白水平的增加， 吸烟者和COPD患者的支气管肺泡灌洗液与不良临床COPD结果。AM是 这种肺细胞外铁的假定来源，因为吸烟者和COPD患者的AM是铁超载的 并在培养中释放铁。我们用免疫组织化学方法复制了AM铁积累和释放的临床现象。 小鼠CS暴露模型。然后，我们使用单细胞RNA测序，发现了新的AM亚群， 其具有与增加的铁摄取一致的独特的铁相关基因表达特征。这些 “铁巨噬细胞”，我们指定为FeMacs，具有与铁巨噬细胞相关的基因表达减少， 吞噬和免疫激活，表明这种CS诱导的AM铁积累可能具有功能性 对AM的后果，以及可能对CS暴露的肺的后果。我们将测试我们的假设，铁马克或- 慢性阻塞性肺疾病中胸部肺损伤的发展，无论是使用我们的小鼠CS模型的机制， 使用SPIROMICS队列。目的1将比较CS引起的小气道损伤和肺气肿的发展- 在对照小鼠和缺乏核受体辅激活因子4（Ncoa 4 Δ Cd 11 c）的AM小鼠之间的差异， 代谢缺陷，减轻CS诱导的铁积累。目的2检查Ncoa 4 Δ Cd 11 c和Ncoa 4fl/fl 对照小鼠在CS-肺炎链球菌感染2-击中模型中，从而确定是否减少 AM铁超载可减轻CS诱导的AM功能障碍，提高对病原体的反应。目标3定义了 AM铁蓄积在人COPD中的临床相关性以及铁基因和AM表达的测试 铁含量作为COPD严重程度的标志物。该提案提出了一个五年职业发展计划， 建立在我以前的研究基础上，并整合了我的指导和咨询的不同专业领域 团队它需要有针对性的培训计划，专门针对与下列方面有关的具体领域的发展： 免疫学，巨噬细胞生物学，铁生物学和转化研究，促进了物理和智能， 由威尔康奈尔医学学院学术环境提供的讲座资源。拟议的实验， 教学培训，以及导师团队将定位我与一套独特的跨学科技能，将 使我能够过渡到独立作为一个物理学家，科学家在肺和巨噬细胞生物学和铁生物学。