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: 10619471
• 负责人: Anna Nolan
• 金额: $ 59.69万
• 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/10619471
• 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) 具有显着的影响 2001 年 9 月 11 日世界贸易中心 (WTC) 的毁坏导致了严重的全球健康负担。 颗粒物 (WTC-PM) 沉积到呼吸消化系统中会导致 WTC 相关疾病。 呼吸道、胃肠道、慢性鼻窦炎、癌症、心理健康问题以及最近的焦点 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)，这完全属于 James Zadroga 9/11 Health 的范围 和赔偿法。 WTC-PM 暴露会导致异质性阻塞性气道疾病 (OAD) 模式，其中包括气道 过度反应 (AHR) 和 FEV1 丧失的早期诊断和治疗选择很少，部分原因是我们的能力有限。 了解其发病机制，而肺血管变化通常被认为是由于以下原因而发生的。 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。 OAD 的血管假说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，例如 代谢综合征、肺动脉/主动脉比率升高和心血管生物标志物（如 CRP）。 WTC-PM 暴露的小鼠模型显示出急性且持续的炎症和 AHR，并反映了 FDNY 第一反应者中观察到的气道和心脏重塑也是 WTC-PM 暴露的持续特征。 因此，在我们的小鼠模型中，我们将重点关注氧化应激介质血红素加氧酶-1 (HO-1)， 已知可刺激胶原蛋白形成，并且在接触 WTC-PM 后也会被诱导。 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 暴露会导致由 HO-1 介导的 WTC-CaRVD。 AHR 将具有 WTC-CaRVD 的功能，并将展示与对照相比独特的生物标志物概况。 该应用的创新方面包括新颖的成像模式和多组学 （放射组/代谢组/甲基组）评估将在三个 AIM 中进行探讨。 AIM 1，我们将探索我们的研究结果在 FDNY WTC 队列中的可转化性 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） 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 通过肌电图和免疫组织学表达血管标志物来确认 HO-1 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 并根据氧化应激介质在 WTC-PM 暴露人群中调整我们的治疗方法。

项目成果

Twenty-Year Reflection on the Impact of World Trade Center Exposure on Pulmonary Outcomes in Fire Department of the City of New York (FDNY) Rescue and Recovery Workers.

世贸中心暴露对纽约市消防局 (FDNY) 救援和恢复人员肺部结果影响的二十年反思。

• 发表时间: 2021
• 影响因子: 5
• 作者: Cleven, Krystal L;Rosenzvit, Carla;Nolan, Anna;Zeig;Kwon, Sophia;Weiden, Michael D;Skerker, Molly;Halpren, Allison;Prezant, David J
• 通讯作者: Prezant, David J

Prehospital hypoxemia, measured by pulse oximetry, predicts hospital outcomes during the New York City COVID-19 pandemic.

通过脉搏血氧仪测量的院前低氧血症可以预测纽约市 COVID-19 大流行期间的医院结果。

• 发表时间: 2021-04
• 作者: Lancet, Elizabeth A;Gonzalez, Dario;Alexandrou, Nikolaos A;Zabar, Benjamin;Lai, Pamela H;Hall, Charles B;Braun, James;Zeig;Isaacs, Douglas;Ben;Reisman, Nathan;Kaufman, Bradley;Asaeda, Glenn;Weiden, Michael D;Nolan, A
• 通讯作者: Nolan, A

COVID-19 Myocarditis: A Case Report, Overview of Diagnosis and Treatment.

COVID-19 心肌炎：病例报告、诊断和治疗概述。

• 发表时间: 2021-11
• 作者: Kwon, Sophia;Alter, Eric;Bangalore, Sripal;Nolan, Anna
• 通讯作者: Nolan, Anna

Author Correction: World Trade Center-Cardiorespiratory and Vascular Dysfunction: Assessing the Phenotype and Metabolome of a Murine Particulate Matter Exposure Model.

作者更正：世界贸易中心-心肺和血管功能障碍：评估小鼠颗粒物暴露模型的表型和代谢组。

• 发表时间: 2021-08-05
• 影响因子: 4.6
• 作者: Veerappan, Arul;Oskuei, Assad;Crowley, George;Mikhail, Mena;Ostrofsky, Dean;Gironda, Zakia;Vaidyanathan, Sandhya;Wadghiri, Youssef Zaim;Liu, Mengling;Kwon, Sophia;Nolan, Anna
• 通讯作者: Nolan, Anna

PEDF, a pleiotropic WTC-LI biomarker: Machine learning biomarker identification and validation.

PEDF，一种多效性 WTC-LI 生物标志物：机器学习生物标志物识别和验证。

• 发表时间: 2021
• 影响因子: 4.3
• 作者: Crowley, George;Kim, James;Kwon, Sophia;Lam, Rachel;Prezant, David J;Liu, Mengling;Nolan, Anna
• 通讯作者: Nolan, Anna