Impact of Biomass Burning Aerosol and Humic-like Substances on Iron Homeostasis and Atherosclerosis

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PROJECT SUMMARY/ABSTRACT Wildfire smoke exposure is thought to be responsible for increased morbidity and 339,000 annual deaths, but little is known about cardiovascular (CV) effects. It is well known that fine particulate matter (PM2.5) is the air pollution component most strongly linked to morbidity and mortality, mostly due to ischemic CV diseases. Extending these effects to biomass burning aerosol (BBA) generated from wildfires is not directly translatable since most studies on CV toxicity of PM2.5 investigate urban PM2.5 which has significant differences in chemical and toxicological profiles compared to BBA. Some suggest BBA exhibits higher CV toxicity compared to non- wildland sources, which may be due to the ability of BBA components to disrupt pulmonary Fe homeostasis. BBA are enriched in atmospheric humic-like substances (HULIS), complex water-soluble organics that have been shown to disrupt pulmonary Fe homeostasis resulting in a functional Fe deficiency that can lead to Fe overload, oxidative stress, and in inflammatory response. Importantly, no study has every investigated the impact of BBA or HULIS exposure on the progression of atherosclerosis. Our central hypothesis is BBA, and HULIS in particular, disrupts Fe homeostasis in pulmonary and systemic tissues leading to increased inflammation and worsened atherosclerosis. In this K99/R00 MOSAIC application, we propose to use laboratory generated BBA in cell culture and controlled in vivo inhalation exposures. In Aim 1, murine alveolar epithelial and alveolar macrophage cultures will be exposed to BBA and HULIS for assessment of changes in Fe homeostasis, oxidative stress, inflammation, and proatherogenic metabolites. We will employ Hepcidin Knockout (HKO) mice as models of Fe overload in alveolar epithelial cells and alveolar macrophages. Aim 2 explores if in vivo BBA exposure exacerbates atherosclerotic lesions in low density lipoprotein receptor knockout (Ldlr-KO) mice on a high fat diet and whether Fe overload in pulmonary and systemic tissues play a role. Aim 1 is proposed to be completed by the candidate under the mentorship of Dr. Jesus Araujo during the K99 phase. Aim 2 will be independently facilitated by the candidate during the R00 phase following appointment to a faculty position. In addition to this research, this K99/R00 MOSAIC will provide support for further training and career development for the candidate. The applicant's long-term goal is to be an independent faculty at a tier-1 university and continue air pollution toxicology research. To achieve this, we propose three training goals for the K99 phase: (1) Enhance Biomedical Education, (2) Develop Skills in In Vitro Methods and (3) Acquire Training in Biostatistics. Dr. Araujo's lab at the David Geffen School of Medicine at UCLA is an ideal environment for successful completion of K99 research as well as achieving training goals and preparing the candidate for saucerful transition to independence. Support in the R00 phase will facilitate the candidate's transition to independence simultaneously advancing the candidate's and NIH diversity goals.