Clec5a regulation of Macrophage function in COPD

Clec5a 对 COPD 巨噬细胞功能的调节

基本信息

批准号：
8696486
负责人：
Michael Borchers
金额：
$ 39.63万
依托单位：
UNIVERSITY OF CINCINNATI
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-04-01 至 2018-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8696486
关键词：
Address Adoptive Transfer Alveolar Macrophages Antibodies Binding C Type Lectin Receptors CCR Cell Line Chimeric Proteins Chronic Bronchitis Chronic Obstructive Airway Disease Coculture Techniques Data Development Disease Disease Progression Economic Burden Epithelial Cells Exhibits Goals Granulocyte-Macrophage Colony-Stimulating Factor Health Immunoprecipitation Inflammation Injury Investigation Laboratories Lead Leukocytes Ligands Lung Macrophage Activation Mass Spectrum Analysis Mediating Modeling Molecular Morbidity - disease rate Mouse Strains Mus NK Cell Activation Oxidative Stress Pathology Pathway interactions Patients Phenotype Play Pneumonia Production Public Health Pulmonary Emphysema Quality of life Receptor Signaling Regulation Reporter Research Respiratory physiology Role Signal Pathway Signal Transduction Smoker Stress Surface Symptoms System Testing Therapeutic Intervention Tissues Up-Regulation Work airway inflammation base chemokine receptor cigarette smoke-induced cigarette smoking cytokine effective therapy macrophage migration monocyte mortality neutrophil novel novel therapeutics public health relevance receptor response

项目摘要

DESCRIPTION (provided by applicant): The health effects and economic burden associated with cigarette smoke (CS) exposure are overwhelming. The primary health effects are associated with symptoms of Chronic Obstructive Pulmonary Disease (COPD) including chronic bronchitis and emphysema. Currently, there are no effective therapies to deter disease progression in COPD patients. Over the last several decades, research has primarily focused on pathologies attributed to oxidative stress and the proteolytic imbalance associated with macrophage and neutrophil functions. Although the significance of these leukocytes and their effector functions are well documented, the mechanisms that lead to their aberrant activation by CS are poorly understood. The goal of our laboratory is to investigate the pathways whereby CS exposure activates pulmonary leukocytes. In this project, we present compelling evidence for a role of the CLEC5A activating receptor in macrophage activation in COPD. Our preliminary studies reveal that CLEC5A, expressed on alveolar macrophage, plays an integral role in macrophage activation following CS exposure. We generated a Clec5a-deficient mouse strain that reveals an essential role for CLEC5A in macrophage activation and pulmonary injury following CS exposure. The Clec5a-deficient mice fail to develop the hallmark features of COPD including pulmonary inflammation, macrophage accumulation and airspace enlargement. Furthermore, using a novel CLEC5A receptor fusion protein and CLEC5A-expressing reporter cell line, we provide evidence that a unique, previously undiscovered ligand for CLEC5A is expressed on CS-exposed pulmonary epithelial cells. These findings suggest a novel mechanism that promotes airway inflammation and pathologies in response to CS exposure.

描述（由申请人提供）：与香烟烟雾（CS）暴露相关的健康影响和经济负担是巨大的。主要的健康影响与慢性阻塞性肺病（COPD）的症状有关，包括慢性支气管炎和肺气肿。目前，尚无有效的疗法来阻止 COPD 患者的疾病进展。在过去的几十年里，研究主要集中在氧化应激以及与巨噬细胞和中性粒细胞功能相关的蛋白水解失衡引起的病理学上。尽管这些白细胞的重要性及其效应器功能已得到充分记录，但导致 CS 异常激活的机制却知之甚少。我们实验室的目标是研究 CS 暴露激活肺白细胞的途径。在这个项目中，我们提出了令人信服的证据，证明 CLEC5A 激活受体在 COPD 巨噬细胞激活中的作用。我们的初步研究表明，肺泡巨噬细胞上表达的 CLEC5A 在 CS 暴露后的巨噬细胞激活中发挥着不可或缺的作用。我们培育了一种 Clec5a 缺陷型小鼠品系，该品系揭示了 CLEC5A 在 CS 暴露后巨噬细胞活化和肺损伤中的重要作用。 Clec5a 缺陷小鼠未能出现慢性阻塞性肺病的标志性特征，包括肺部炎症、巨噬细胞积聚和空腔扩大。此外，使用新型 CLEC5A 受体融合蛋白和表达 CLEC5A 的报告细胞系，我们提供了证据表明，一种独特的、以前未发现的 CLEC5A 配体在暴露于 CS 的肺上皮细胞上表达。这些发现表明了一种新的机制，可以促进气道炎症和病理学，以响应 CS 暴露。