RAGE Mediates LPA Induced Pulmonary Inflammation

RAGE 介导 LPA 引起的肺部炎症

基本信息

批准号：
8962412
负责人：
Anna Nolan
金额：
$ 41.68万
依托单位：
NEW YORK UNIVERSITY SCHOOL OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-09-07 至 2020-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8962412
关键词：
Acute Advanced Glycosylation End Products Agonist Anti-Inflammatory Agents Anti-inflammatory Attenuated Binding Biological Assay Biological Markers Biological Preservation Biomass Blood Vessels Bone Marrow Transplantation Bronchoalveolar Lavage Cell Extracts Chronic lung disease Complement Conflict (Psychology)Data Defect Developed Countries Developing Countries Development Diet Disasters Disease Early treatment Evaluation Evolution Exposure to FDA approved Fatty acid glycerol esters Fire - disasters Forced expiratory volume function Functional disorder Grant Health High Prevalence Histology Hour IL8 gene In Vitro Inflammation Inflammation Mediators Inflammatory Injury Interleukin-10 Investigation Late Effects Link Lipids Low-Density Lipoproteins Lung Lung Inflammation Lung diseases Lysophosphatidic Acid Receptors Lysophospholipids Measures Mediating Mediator of activation protein Metabolic Metabolic Diseases Metabolic syndrome Military Personnel Modeling Mus Nested Case-Control Study Neutrophilia New York Obstructive Lung Diseases PPAR gamma Particulate Particulate Matter Pathway interactions Patients Peritoneal Macrophages Pioglitazone Plasma Population Prevalence Pulmonary Function Test/Forced Expiratory Volume 1 Pulmonary Inflammation Relative Risks Reporting Research Resistance Respiratory physiology Retroviridae Risk Factors Role Route Sample Size Sampling Series Serum Signal Transduction Single Nucleotide Polymorphism Smoke Smoking History Spirometry Stimulus Time Wild Type Mouse Work airway hyperresponsiveness biobank clinical phenotype cohort cytokine disease diagnosis emergency service responder gain of function genome wide association study hazard in vivo insight intraperitoneal irradiation lung injury lysophosphatidic acid macrophage methacholine novel oxidation public health relevance receptor reconstitution research study vascular inflammation

项目摘要

DESCRIPTION (provided by applicant): Development of ventilatory dysfunction following particulate matter (PM) exposure is a major health concern worldwide. Industrialized and developing nations have high ambient particulates and a coexisting high prevalence of metabolic syndrome (MetSyn). The contribution of these two conditions to obstructive pulmonary disease is a topic of considerable importance. The collapse of the World Trade Center (WTC) exposed over 11,000 FDNY first responders to high concentration particulate matter (WTC-PM) at a defined point in time. Between 10/2001-2/2002, serum was obtained on over 8,000 exposed FDNY first responders and is available for biomarker investigation. Since this biobank was obtained prior to disease diagnosis, the biomarkers are not caused by the disease and could reflect pathogenic pathways active during disease evolution. Our research has demonstrated that mediators of MetSyn predict abnormal forced expiratory volume in one second (FEV1) over the subsequent six years. This effect is independent of confounders such as BMI. To better dissect which component of MetSyn contribute to this effect we investigated Lysophosphatidic acid (LPA), a metabolic product of LDL. We recently reported LPA level predicts developing an abnormal FEV1. Our collaborator Dr. Schmidt has defined RAGE as a receptor for LPA. RAGE is highly expressed in the lung and is a strong predictor of FEV1 in genome wide association studies. Our preliminary murine experiments show that WTC-PM exposure produces neutrophilia, loss of FEV1, increased resistance and methacholine reactivity. RAGE deficient mice are protected from these WTC-PM effects. Pioglitazone, an FDA-approved PPARɣ agonist, inhibits RAGE signaling and was studied as a potential treatment against PM-induced inflammation. Our preliminary data showed that it protects against WTC-PM-induced increased resistance, FEV loss, and neutrophilia, but not against airway hyperreactivity. Hypothesis: RAGE mediates LPA induced lung inflammation. Increased LPA interacts with PM to promote greater inflammation than either stimulus alone. Pioglitazone can attenuate PM-induced lung injury. Our hypothesis will be explored in 3 aims. Aim 1 extends our biomarker observations to 1720 symptomatic patients who presented for evaluation before 2008. Aim 2 will use a series of loss/gain of function experiments in murine and macrophage models to dissect the contribution of RAGE to PM/LPA interaction. Aim 3 investigates if pioglitazone treatment attenuates early and late effects of PM-induced pulmonary inflammation via RAGE. Data generated by this grant will provide new insights into the novel role of RAGE in mediating the interaction between metabolic syndrome and pulmonary dysfunction, bringing us closer to new therapies for obstructive lung disease.

描述（由申请人提供）：接触颗粒物 (PM) 后出现的通气功能障碍是全球范围内的一个主要健康问题。工业化国家和发展中国家的环境颗粒物浓度较高，代谢综合征 (MetSyn) 的患病率也很高。世界贸易中心 (WTC) 的倒塌使 11,000 多名纽约消防局急救人员暴露在高浓度颗粒物的环境中。 (WTC-PM) 在 2001 年 10 月至 2002 年 2 月期间，从超过 8,000 名暴露的 FDNY 急救人员中获得了血清，并且可用于生物标志物研究，因为该生物库是在疾病诊断之前获得的。不是由疾病引起的，并且可以反映疾病进化过程中活跃的致病途径。我们的研究表明，MetSyn 的介质可以预测未来六年的异常用力呼气量 (FEV1)。这种效应与 BMI 等混杂因素无关，为了更好地剖析 MetSyn 的哪些成分会导致这种效应，我们研究了 LDL 的代谢产物——溶血磷脂酸 (LPA)，我们的合作者 Dr. Schmidt 将 RAGE 定义为 LPA 的受体。在全基因组关联研究中，RAGE 是 FEV1 的有力预测因子。产生中性粒细胞增多、FEV1 丧失、抵抗力增加和 RAGE 缺陷小鼠免受这些 WTC-PM 的影响。吡格列酮是 FDA 批准的 PPARɣ 激动剂，可抑制 RAGE 信号传导，并被研究为对抗 PM 引起的炎症的潜在治疗方法。我们的初步数据表明，它可以防止 WTC-PM 引起的阻力增加、FEV 降低和中性粒细胞增多，但不能防止气道高反应性假设：RAGE。增加的 LPA 与 PM 相互作用，比单独使用吡格列酮可以减轻 PM 引起的肺损伤，我们的假设将在 3 个目标中进行探索，将我们的生物标志物观察扩展到 1720 名有症状的患者。 2008 年之前进行评估。目标 2 将在小鼠和巨噬细胞模型中使用一系列功能丧失/获得的实验来剖析 RAGE 对 PM/LPA 的贡献目标 3 研究吡格列酮治疗是否可以通过 RAGE 减轻 PM 诱导的肺部炎症的早期和晚期影响。这项资助产生的数据将为 RAGE 在介导代谢综合征和肺功能障碍之间的相互作用中的新作用提供新的见解。更接近阻塞性肺病的新疗法。