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 W...