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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要慢性阻塞性肺疾病（COPD）是一种与吸烟相关的呼吸系统疾病，是第三大主要疾病。气道和肺泡巨噬细胞功能障碍的数量增加。 (AM) 存在于吸烟者和慢性阻塞性肺病患者的肺部，定位于损伤区域。香烟烟雾 (CS) 如何引起 AM 功能障碍背后的机制，以及 AM 功能障碍如何促进小气道疾病和肺气肿是慢性阻塞性肺病的两个典型特征，但人们对它的发展知之甚少。该提案解决了这一知识上的关键差距，并检验了慢性阻塞性肺病 (COPD) 中的 AM 功能障碍是使用多中心前瞻性慢性阻塞性肺病在机制上与这些细胞中的异常铁积累有关。（SPIROMICS）队列中，我们之前将支气管中铁和铁相关蛋白水平的增加与吸烟者和具有不良临床 COPD 结局的 COPD 患者的肺泡灌洗液是 AM 的样本。这种肺细胞外铁的假定来源，因为吸烟者和慢性阻塞性肺病患者的 AM 铁含量超载我们使用 AM 铁积累和释放的临床现象进行了复制。然后我们使用单细胞 RNA 测序发现了新的 AM 子集。它们具有独特的铁相关基因表达特征，与铁吸收的增加一致。 “铁巨噬细胞”，我们将其命名为 FeMacs，其相关基因的表达降低吞噬作用和免疫激活，表明 CS 诱导的 AM 铁积累可能具有功能性对于 AM 的后果，以及可能对暴露于 CS 的肺部的后果，我们将检验我们的假设，即 FeMac 或 - 慢性阻塞性肺病 (COPD) 中胸部肺损伤的发展，无论是使用我们的小鼠 CS 模型还是转化机制使用 SPIROMICS 队列，目标 1 将比较 CS 引起的小气道损伤和肺气肿的发展。对照小鼠和缺乏核受体辅激活因子 4 (Ncoa4ΔCd11c)（一种铁）的 AM 小鼠之间的实验代谢缺陷可减轻 CS 诱导的铁积累，目标 2 检查 Ncoa4ΔCd11c 和 Ncoa4fl/fl。在CS-肺炎链球菌感染2次打击模型中对照小鼠，从而确定是否减少 AM 铁过载可以缓解 CS 引起的 AM 功能障碍并改善对病原体定义的反应。 AM 铁积累在人类 COPD 中的临床相关性并测试 AM 铁基因和 AM 的表达铁含量作为慢性阻塞性肺病严重程度的标志该提案提出了一个五年职业发展计划以我之前的研究为基础，整合了我的指导和咨询的不同专业知识领域它需要针对特定领域的发展制定有针对性的培训计划。免疫学、巨噬细胞生物学、铁生物学和转化研究，由物理和智力促进威尔康奈尔医学院的学术环境提供的学术资源拟议的实验，教学培训以及导师团队将使我具备一套独特的跨学科技能，这些技能将使我能够作为肺和巨噬细胞生物学以及铁生物学领域的医师科学家过渡到独立。