PROJECT SUMMARY. This K01 grant proposal will investigate the early vascular injury and end organ dysfunction in World Trade Center (WTC)-Particulate Matter (WTC-PM) exposed and affected by gastroesophageal reflux disease (GERD). PM is the main component of WTC dust, and the exposure of WTC- PM includes effects such as systemic inflammation, vascular dysfunction, and subsequent end-organ damage. Epidemiologic investigations have documented associations between increased PM, lung, cardiovascular and kidney diseases such as chronic kidney diseases (CKD). Additionally, metabolic syndrome (MetSyn) is often associated with kidney damage, and we have seen MetSyn in a large population of our Fire Department of New York (FDNY) study cohort. This leads to the possible risk of end organ damage such as cardio-renal disease in WTC-PM exposed FDNY first responders. Further, CKD remains one of the leading causes of mortality and are characterized by a marked and reduction of renal artery flow. This yields tissue ischemia, renal injury and fibrosis. Hence, there is an urgent need to explore relevant early phenotypic changes and identify related kidney biomarkers and cardio-renal vascular setting. Further, a greater understanding of the cellular and molecular mechanisms underlying cardio-renal injury could lead to the development of new therapeutic approaches. This proposal will focus on exploring cardio-renal/ vascular injury biomarkers in FDNY cohort serum samples as well as understanding the role of macrophages and transforming growth factor-beta (TGF-β) in the development of renal vascular dysfunction (RVD) in WTC-PM–exposed GERD model, and subsequent cardio-renal failure in this murine model. Earlier studies showed that immune cells in particular macrophages play a critical role in mediating cardio-renal injury, repair, and fibrosis. Interestingly, our recent preliminary work shows that there is macrophage hyperplasia in WTC-PM exposed mice with loss of lung function. Fibrosis is the hallmark of progressive CKD, which leads to an end organ failure. Our earlier studies indicate that activation of inflammatory cells can mediate fibrosis in both the heart and kidney through TGF-β. Our preliminary findings demonstrate that with an increased inflammation, and collagen deposition in inter-tubular region in the kidneys. This proposal consists of 3 aims. Aim 1 will quantify WTC-cardio-renal vascular risk biomarkers from first responders (FDNY). Aim 2 will further determine cardio-renal vascular injury by quantifying functional/histopathologic and complementary imaging modalities in a murine WTC-PM exposure model. Aim 3 will further assess whether WTC-PM induced cardio-renal vascular injury has an influence in a GERD murine model. Results of the proposed research will help provide insights into WTC-PM induced cardio-renal associated with GERD risk biomarkers in first responders as well as how macrophage and TGF-β influence RVD in the remodeling of WTC-PM -induced ca...