PROJECT SUMMARY AND ABSTRACT From the 1940s-1980s, corporate uranium (U) mines were established in the Southwestern United States, many on Native American lands. Due to improper reclamation and poor remediation, surrounding residential homes are subject to residual mixed-metals exposure including arsenic (As), vanadium (V), uranium (U), and nickel (Ni) via ingestion and inhalation. Inhaled metal-based derived particulate matter (PM) has been associated with an increase in circulating serum inflammatory potential and subsequent vascular and neurovascular disease. The full scope of systemic health effects following inhaled mine-site derived PM has yet to be elucidated and the role of circulating factors, such as small extracellular vesicles (sEVs) in driving inflammatory impacts is underexplored. In preliminary studies, we have observed that mine-site PM is more acutely toxic to pulmonary and vascular systems than regional ‘background’ PM. Furthermore, similar studies of inhaled particulates and gases demonstrate endothelial dysfunction that can drive vascular dysfunction and inflammatory outcomes. Therefore, my specific aims will serve three primary objectives 1) mechanistically delineate lung-sEV biogenesis following PM exposure 2) mechanistically evaluate sEV endocytosis following PM exposures and 3) assess associations between type of mining dust exposure (U-mining vs. non-U mining) and sEV vascular biomarkers in an established human cohort of former miners (the MiDUS cohort, Mining Dust in the United States). This proposal serves as an innovative, five-year research project to understand the mechanistic role of sEVs in driving toxic responses following PM exposure. We shall leverage the outstanding facilities and resources at the University of New Mexico – Health Sciences Center, including the Autophagy, Inflammation and Metabolism (AIM) Center (P20GM121176), the University of New Mexico Center for Metals in Biology and Medicine (P20GM130422), the UNM Mobile Epidemiology Laboratory (MEL) and our long-standing collaborations with community partners, including the Miners’ Colfax Medical Center Mobile Outreach. With global extraction of metal ores surging due to increased demand for batteries, computer chips and energy, environmental mixed-metals exposure has become an issue of concern in both an occupational and environmental context. Data from these studies will ultimately lead to essential information pertinent to metal- exposed populations, as well as governing agencies involved in air-quality regulations.