Particulate Matter-Induced Pulmonary Exosomes and the Lung-Brain Axis

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PROJECT SUMMARY AND ABSTRACT Corporate uranium mines were established in the Southwestern United States from the 1940s-1980s, leaving behind poorly remediated sites near surrounding residential homes. Inhaled, mine-site derived particulate matter (PM) has been associated with an increase in serum inflammatory potential and subsequent vascular and neurological disease. The PM arising from these uranium mines tends to be high in specific toxic, inorganic metals including vanadium (V), uranium (U), and often nickel (Ni) and arsenic (As). The full scope of systemic health effects following inhaled mine-site derived PM is unknown, but such inflammatory impacts to the neurovasculature could promote neurological diseases and the elucidation of such mechanisms has yet to be discerned. Therefore, the primary objective of this research proposal is to develop a deeper understanding of the mechanistic, causal basis for mine-site derived PM-induced neurovascular dysfunction. In preliminary studies, we have observed that mine site PM is more acutely toxic to the lungs and brain compared to regional background PM. Furthermore, similar studies of inhaled particulates and gases demonstrate a BBB dysfunction that can drive neuroinflammatory outcomes. Therefore, my specific aims will serve two primary objectives: 1) mechanistically delineate the contribution of circulating PM-induced exosomes as drivers of cerebrovascular endothelial barrier dysfunction and neuroinflammation. 2) quantitatively assess endothelial cell dynamics following treatment with circulating exosomes from PM-exposed mice using high-content, single-cell imaging. This proposal will serve as a high-risk, high reward project in a supportive academic environment where investigators can take advantage of several shared resources. We will take full advantage of the outstanding facilities at the University of New Mexico Health Sciences Center, including the Brain and Behavioral Health Institute (BBHI) and the Biomedical Research and Integrative Neuroimaging Center (BRaIN), where the MRI, is housed. Data from these studies will ultimately lead to essential information pertinent to Southwestern populations in close proximity to abandoned uranium mines, as well as governing agencies involved in air-quality regulations.