University Of California-Davis receives $2.8M Cardiovascular Diseases Research grant from the National Institutes of Health

Wildfire exposure: cardiovascular and airway inflammation research (we-cair) - overall summary wildfire smoke exposure is now recognized as a major contributor to cardiovascular and copd exacerbations. However, the long-term consequences, cellular-molecular mechanisms, risk factors, and biomarkers of disease severity remain unknown. Through the “wildfire exposure – cardiovascular and airway inflammation research (we-cair)” program our interdisciplinary team with long-standing collaborative relationships aims to address this knowledge gap. Our preliminary studies in healthy volunteers and copd patients as well as in mouse models suggest a role for group 2 innate lymphoid cells (ILC2) in wildfire smoke-induced inflammation. Investigations into the aryl hydrocarbon receptor (ahr) and the epigenetic regulatory enzyme ten-eleven translocation methylcytosine dioxygenase 1 (TET1) revealed potential epigenetic and transcriptional modifications of airway inflammation. Psychological stress significantly contributes to glucocorticoid resistance and worsening of cardiovascular and airway disease potentially through convergent epigenetic pathways. We postulate that wildfire smoke exposure coupled with psychological stress induces non-canonical il-17 expression in ILC2 by altering the ahr/TET1/2 axis through epigenetic and transcriptional regulation that accelerates lung function decline in copd and cardiovascular disease. Goal i: to understand how non- canonical il-17 production in ILC2 via the impaired ahr/TET1 axis mediates the effects of wildfire smoke and psychological stress on inflammatory cardiovascular and airway disease. We will investigate the role of ILC2 (project 1), ahr (project 2), TET1 (project 3), and stress (project 4) in mouse models of simulated wildfire smoke exposure (core c) and human copd and healthy subjects with a history of high or low levels of wildfire smoke exposure (core d). Goal II: elucidate the role and extent of epigenetic regulation of the wildfire smoke effects. Epigenetic memory and ahr/TET1/2 cross-regulation of the IL17A promoter plasticity and other novel candidate mechanisms mediating wildfire smoke exposure and stress effects will be studied in human peripheral blood, nasal epithelium and sputum and blood, nasal cells and lung tissue from mouse models (core b, project 3). Goal III: determine the potential therapeutic and predictive significance of il-17+ILC2 and other candidate (epigenetic, molecular, cellular, and behavioral) signatures in wildfire-smoke induced severity, and long-term effects on copd. Innovative systems level integration and machine learning techniques (core a, core b) will analyze the clinical, behavioral, exposure, and biospecimen-derived epigenetic, cellular and molecular data derived from cores c, d and projects 1-4. The we-cair program's strength lies in its novel hypothesis, interdisciplinary approach, centralized experimental design and data processing across all projects supported by cutting edge epigenetics, engineering and bioinformatics technology. By fostering collaboration among interdisciplinary colleagues and supporting emerging scientific leaders, the program will drive innovation and advance research in the fields of pulmonary, cardiovascular, and environmental health.