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

摘要 颗粒物(PM)相关的心肺和血管功能障碍(CARVD)构成显著的 全球健康负担。2001年9月11日世贸中心(WTC)的破坏导致了一场激烈的 颗粒物沉积(WTC-PM)进入空气消化系统。与WTC相关的疾病包括 呼吸道、胃肠道、慢性鼻-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。我们的提案将调查WTC-心肺疾病的发展 和血管功能障碍(WTC-CARVD)，这坚定地属于詹姆斯·扎德罗加9/11健康的职权范围 和补偿法。 暴露于WTC-PM会导致不同类型的阻塞性呼吸道疾病(OAD)，其中包括呼吸道 高反应性(AHR)和FEV1丢失。早期诊断和治疗选择很少，部分原因是我们的 对其发病机制的了解。虽然传统上认为肺血管改变是由于 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的血管假说认为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增加，如 代谢综合征，肺动脉/主动脉比值升高，以及心血管生物标志物(如CRP)。 WTC-PM暴露的小鼠模型显示炎症、AHR明显和持续存在，并反映了 在纽约联邦储备银行第一响应者中看到。呼吸道和心脏重构也是WTC-PM暴露的持久特征 在我们的小鼠模型中。因此，我们将重点关注氧化应激的介体--血红素加氧酶-1(HO-1)。 已知可刺激胶原形成，也可在WTC-PM暴露后诱导。此外，路径和 WTC-CARVD的机制值得进一步研究，也是我们5年计划的重点。 我们的假设是WTC-PM暴露引起由HO-1介导的WTC-CARVD。第一响应者与 AHR将具有WTC-CARVD的特征，并将展示与对照相比独特的生物标记物特征。 该应用的创新方面包括新的成像模式和多OMIC (放射组/代谢组/甲基组)评估。这些假设将从三个方面进行探讨。 目的1，我们将探索我们的研究结果在纽约世界贸易中心队列中的可译性。AIM-2 Will表型血清 生物标志物/代谢物、表观遗传学、组织学和活体成像(超声心动图、核磁共振和µPET/µCT) WTC-CARVD。此外，我们将利用HO-1基因缺陷的小鼠，并外源性减弱HO-1 在我们的小鼠WTC-PM模型中，AIM 2和AIM 3将量化终末器官受累和功能丧失/获得 通过肌电图和免疫组织化学血管标志物的表达来检测HO-1。确认以下内容的相关性 WTC-PM相关的AHR的血管和呼吸道重构将使我们能够专注于早期发现 并在WTC-PM暴露的氧化应激介体队列中定制我们的治疗方法。

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.