World Trade Center Particulate Matter Induced Cardiorespiratory and Vascular Dysfunction: a MultiOmic Approach

世界贸易中心颗粒物引起的心肺和血管功能障碍：多组学方法

• 批准号: 10315661
• 负责人: Anna Nolan
• 金额: $ 59.2万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-01 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10315661
• 关键词: World; Trade; Center; Particulate; Matter

SUMMARY Particulate matter (PM) associated cardiorespiratory and vascular dysfunction (CaRVD) poses a significant global health burden. The World Trade Center (WTC) destruction on September 11, 2001 led to an intense deposition of particulate matter (WTC-PM) into aerodigestive system. WTC associated morbidities include respiratory, gastrointestinal, chronic rhinosinusitis, cancer, mental health concerns and more recently a focus has been on cardiovascular disease. Our proposal will investigate the development of WTC-cardiorespiratory and vascular dysfunction (WTC-CaRVD) which is firmly within the purview of the James Zadroga 9/11 Health and Compensation Act. WTC-PM exposure causes heterogeneous obstructive airways disease (OAD) patterns, which include airway hyperreactivity (AHR) and loss of FEV1. Early diagnosis and therapeutic options are few, in part due to our limited understanding of their pathogenesis. While pulmonary vascular changes are classically thought to occur due to the hypoxemia of late OAD, recent investigations show that vascular dysfunction occurs early in OAD. This vascular hypothesis of OAD postulates that pulmonary vasculature remodeling leads to loss of lung function. Early evidence of WTC-CaRVD includes increased prevalence of cardiovascular disease risk factors such as metabolic syndrome, elevated pulmonary artery/aorta ratio, and cardiovascular biomarkers (such as CRP). Murine models of WTC-PM exposure show inflammation, AHR both acutely and persistently and reflect what is seen in FDNY 1st responders. Airway and cardiac remodeling were also persistent features of WTC-PM exposure in our murine models. Therefore, we will focus on Heme Oxygenase-1 (HO-1), a mediator of oxidative stress, known to stimulate collagen formation and is also induced after WTC-PM exposure. Furthermore, pathways and mechanisms of WTC-CaRVD warrant further study and are the focus of our 5-year proposal. Our HYPOTHESIS is that WTC-PM exposure causes WTC-CaRVD mediated by HO-1. First responders with AHR will have features of WTC-CaRVD, and will demonstrate a unique biomarker profile compared to controls. Innovative aspects of this application include novel imaging modalities and multiOmic (radiome/metabolome/methylome) assessments. These hypotheses will be explored in three AIMs. AIM 1, we will explore the translatability of our findings in the FDNY WTC cohort. AIM 2 will phenotype serum biomarkers/metabolites, epigenetics, histology and in vivo imaging (echocardiography, MRI, and µPET/µCT) of WTC-CaRVD. Furthermore, we will utilize mice genetically deficient in HO-1 and exogenously attenuate HO-1 in our murine WTC-PM model, AIM 2 and 3. AIM 3 will quantify end organ involvement and loss/gain of function of HO-1 by myography and immunohistologic expression of vascular markers. Confirmation of the relevance of the vascular and airway remodeling of WTC-PM associated AHR would allow us to then focus on early detection and tailor our therapeutics in the WTC-PM exposed cohorts on mediators of oxidative stress.

概括 颗粒物（PM）相关的心肺和血管功能障碍（CARVD）具有显着 全球健康伯恩。 2001年9月11日，世界贸易中心（WTC）的破坏导致了强烈的 将特定物质（WTC-PM）沉积到气化系统中。 WTC相关的病因包括 呼吸道，胃肠道，慢性鼻孔炎，癌症，心理健康问题以及最近的重点 一直患有心血管疾病。我们的建议将调查WTC - 心脏呼吸系统的发展 和血管功能障碍（WTC-CARVD），首先在詹姆斯·扎德罗加（James Zadroga）9/11 Health的权限范围内 和赔偿法。 WTC-PM暴露会导致异质阻塞气道疾病（OAD）模式，其中包括气道 过度反应性（AHR）和FEV1的丢失。早期诊断和治疗选择很少，部分原因是我们有限 了解它们的发病机理。虽然经典地认为肺血管变化是由于 OAD晚期缺氧，最近的调查表明，血管功能障碍发生在OAD早期。这 OAD的血管假设假设肺血管重塑导致肺功能丧失。 WTC-CARVD的早期证据包括心血管疾病危险因素的患病率增加 代谢综合征，肺动脉/主动脉比率升高和心血管生物标志物（例如CRP）。 WTC-PM暴露的鼠模型显示注射，AHR敏锐而持久地反映了什么 在FDNY第一响应者中看到。气道和心脏重塑也是WTC-PM暴露的持续特征 在我们的鼠模型中。因此，我们将专注于血红素氧酶-1（HO-1），这是氧化应激的介体， 已知会刺激胶原蛋白形成，并且在WTC-PM暴露后也会诱导。此外，路径和 WTC-CARVD的机制需要进一步研究，并且是我们5年提案的重点。 我们的假设是WTC-PM暴露会导致HO-1介导的WTC-CARVD。第一响应者 AHR将具有WTC-CARVD的功能，并且与对照组相比将展示独特的生物标志物概况。 该应用程序的创新方面包括新型成像方式和多构想 （放射线/代谢组/甲基组）评估。这些假设将在三个目标中探讨。 AIM 1，我们将在FDNY WTC队列中探索我们发现的转换性。 AIM 2将表型串行 生物标志物/代谢物，表观遗传学，组织学和体内成像（超声心动图，MRI和µPET/µCT） WTC-CARVD。此外，我们将利用通常缺乏HO-1的小鼠，外源衰减HO-1 在我们的Murine WTC-PM模型中，AIM 2和3。AIM3将量化最终器官的参与和功能的损失/增益 Mohaphing和血管标记的免疫组织学表达的HO-1。确认相关性 WTC-PM相关AHR的血管和气道重塑将使我们能够重点放在早期检测上 并根据氧化应激介体暴露的队列量身定制我们的治疗剂。