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（由适用提供）：在特定问题（PM）暴露之后的通风功能障碍的发展是全世界的主要健康问题。工业化和发展中国家具有较高的环境成分，并且存在代谢综合征（METSYN）的高流行率。这两种情况对阻塞性肺部疾病的贡献是一个考虑重要性的话题。世界贸易中心（WTC）的崩溃在定义的时间点暴露于11,000个FDNY第一响应者对高浓度颗粒物（WTC-PM）的崩溃。在10/2001-2/2002之间，在8,000多个暴露的FDNY急救人员中获得了血清，可用于生物标志物研究。由于该生物库是在疾病诊断之前获得的，因此生物标志物不是由疾病引起的，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的调解人在随后的六年中预测一秒钟（FEV1）的强迫到期量异常。这种效果与BMI等混杂因素无关。为了更好地剖析Metsyn的哪个成分有助于这种效果，我们研究了LDL的代谢产物溶血磷脂酸（LPA）。我们最近报道了LPA水平预测产生异常FEV1的预测。我们的合作者Schmidt博士将Rage定义为LPA的受体。愤怒在肺中高度表达，是基因组广泛关联研究中FEV1的有力预测指标。我们的初步鼠实验表明，WTC-PM暴露会产生嗜中性粒细胞，FEV1的丧失，耐药性增加和甲基苯胺反应性。愤怒不足的小鼠受到这些WTC-PM效应的保护。 Pioglitazone是FDA批准的PPARɣ激动剂，抑制了愤怒信号，并被研究为对PM诱导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诱导的抗药性增加，FEV丢失和中性粒细胞，但不能防止气道高反应性。假设：愤怒介导LPA诱导的肺部感染。与单独使用任何一种刺激相比，LPA增加与PM相互作用以促进炎症。吡格列酮可以减弱PM诱导的肺损伤。我们的假设将在3 AIM 1中进行探讨，将我们的生物标志物观察延伸到2008年之前进行评估的1720名有症状的患者。AIM2将使用鼠和巨噬细胞模型中的一系列功能实验损失/获得实验来剖析愤怒对PM/LPA相互作用的贡献。 AIM 3研究了吡格列酮治疗是否会通过愤怒降低PM诱导的肺部炎症的早期和晚期作用。该赠款产生的数据将为愤怒在介导代谢综合征与肺部功能障碍之间相互作用中的新作用提供新的见解，从而使我们更接近用于阻塞性肺部疾病的新疗法。