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.

总结 颗粒物（PM）相关的心肺和血管功能障碍（CaRVD）造成了显著的 全球健康负担。2001年9月11日，世界贸易中心（WTC）被摧毁， 颗粒物（WTC-PM）沉积到呼吸消化系统。WTC相关疾病包括 呼吸道、胃肠道、慢性鼻窦炎、癌症、精神健康问题，以及最近的一个焦点 一直在研究心血管疾病我们的建议将调查WTC的发展-心肺 和血管功能障碍（WTC-CaRVD），这完全属于James Zadroga 9/11 Health的范围 和赔偿法。 WTC-PM暴露导致异质性阻塞性气道疾病（OAD）模式，包括气道 高反应性（AHR）和FEV 1损失。早期诊断和治疗选择很少，部分原因是我们有限的 了解其发病机制。虽然肺血管变化通常被认为是由于 晚期OAD的低氧血症，最近的研究表明，血管功能障碍发生在OAD的早期。这 OAD的血管假说假定肺血管重构导致肺功能丧失。 WTC-CaRVD的早期证据包括心血管疾病风险因素的患病率增加，例如 代谢综合征、肺动脉/主动脉比值升高和心血管生物标志物（如CRP）。 WTC-PM暴露的小鼠模型显示急性和持续的炎症、AHR，并反映了 在纽约消防局第一反应人员中发现的气道和心脏重塑也是WTC-PM暴露的持续特征 in our murine鼠models模型.因此，我们将重点关注血红素加氧酶-1（HO-1），一种氧化应激介质， 已知刺激胶原蛋白形成，并且在WTC-PM暴露后也被诱导。此外，路径和 WTC-CaRVD的机制值得进一步研究，也是我们5年提案的重点。 我们的假设是WTC-PM暴露导致HO-1介导的WTC-CaRVD。第一反应者， AHR将具有WTC-CaRVD的特征，并且与对照相比将显示独特的生物标志物特征。 该应用的创新方面包括新型成像模式和multiOmic （放射性组/代谢组/甲基化组）评估。这些假设将在三个目标实施办法中加以探讨。 目的1，我们将探讨我们的研究结果在FDNY WTC队列中的可翻译性。AIM 2将表型血清 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HO-1基因缺陷的小鼠和外源性减毒HO-1 在我们的鼠WTC-PM模型中，AIM 2和3. AIM 3将量化终末器官受累和功能丧失/获得 通过肌造影和血管标记物的免疫组织学表达检测HO-1的表达。确认《公约》的相关性 WTC-PM相关AHR的血管和气道重塑将使我们能够专注于早期检测 并在WTC-PM暴露队列中调整我们的治疗方法，以调节氧化应激。