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The major focus of research in our group is P450- and cyclooxygenase-derived eicosanoids, with an emphasis on how they function in the respiratory and cardiovascular systems. The P450 work has been driven by two hypotheses: (1) cytochromes P450 metabolize arachidonic acid to eicosanoids that play critical roles in modulating fundamental biological processes; and (2) aberrant P450 expression and/or function due to environmental or genetic factors leads to altered production or removal of bioactive eicosanoids and results in cell/organ dysfunction and disease. Our group has identified a number of P450s that are active in the metabolism of arachidonic acid to epoxyeicosatrienoic acids (EETs) in the respiratory and cardiovascular systems. We have also shown that soluble epoxide hydrolase (sEH) is the main enzyme involved in EET removal. EETs possess a myriad of biological effects and are involved in the regulation of vascular and airway tone, inflammation, and response to environmental stressors such as ischemia. We have developed new transgenic and knockout murine models to study the effects of EET biosynthesis and metabolism on respiratory and cardiovascular function. Opportunities for translational research in this area include development of novel therapeutics for management of hypertension, atherosclerosis, ischemic heart disease and inflammatory diseases of the lung. Identification of individuals at increased risk for these disorders due to genetic variation may also lead to new approaches to prevention of pulmonary and cardiovascular disease. The cyclooxygenase work focuses on the role of prostaglandins in regulating lung function under both normal and pathological conditions. Work in this area is based on the hypothesis that cyclooxygenase-derived eicosanoids are important modulators of the lung immune response to environmental agents such as allergens, respiratory viruses and bacterial lipopolysaccharide. The group has utilized cyclooxygenase knockout mice and developed cyclooxygenase transgenic animals to study the effects of altered prostaglandin biosynthesis in the lung. The studies in this area will lead to additional opportunities for both mechanistic and translational research in environmental lung diseases.
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FASEB journal : official publication of the Federation of American Societies for Experimental Biologyno. 7 (2023)
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