Abstract:Vanadium is a ductile and malleable transition metal and has a wide application in a range of industries such asautomotive aerospace chemistry and agriculture industries. A great amount of the environmental vanadiumcomes from human activity particularly burning of crude oil and coal as well as metallurgic and mining activities.The major risk for human exposure to vanadium is through inhalation of particulate matter (PM) generated byfuel combustion. Occupational exposure to vanadium pentoxide (V2O5) in humans were reported to link to asthmaand chronic bronchitis. Furthermore increased vanadium concentration in ambient PM2.5 was found to associatewith asthma and asthma exacerbation in young children. The prominent features of asthma and chronicbronchitis include inflammation and mucus hypersecretion. We reported that respiratory exposure to V2O5caused inflammation and airway mucous cell metaplasia (MCM) a significant increase of mucous cell numbercausing mucus hypersecretion in a mouse model of Vanadium Induced Pulmonary Toxicity (VIPT) supportingthe observational finding from human exposure. In the present study we have identified a quantitative trait locuson mouse chromosome 11 containing Ppp3r1 a regulatory component of calcineurin (CN) which wassignificantly associated with vanadium induced MCM. We further demonstrate that CN inhibition by CyclosporineA rendered the susceptible A/J mice resistant to VIPT. Thus we plan to test a novel hypothesis that CN may bean important determinant of the susceptibility to VIPT that particularly affects airway epithelium a critical barrierand innate immune regulator in almost all lung illnesses. Thus we propose to first determine the mechanisticrole of CN in mediating susceptibility to VIPT using both gain-of-function CN model and CN inhibition model(Aim1). We will also extend our preliminary study that was performed mainly in a high-dose acute V2O5 model toa novel long-term inhalational model that is close to real-life environmental vanadium exposure. We willdetermine the role of CN in mediating long-term VIPT (Aim2). Successful completion of this proposal will advanceour understanding of how vanadium interacts with pulmonary system and elicits toxicity. Additionally it will bealso highly translatable as our novel findings and novel models will inform new therapeutic target for the chroniclung diseases characterized by mucous hypersecretion such as asthma chronic bronchitis etc. which are alsothe major illnesses caused by vanadium exposure.