Cytochrome P450 (CYP) monooxygenases oxidize a large variety of nutritive and non-nutritive lipids including man-made xenobiotics to reduce toxicity and increase their elimination. The expression of individual P450 enzymes is controlled by a variety of hormonal and metabolic inputs as well as by xenobiotics.
The specific aims of this project focus on the regulation and function of human CYP4A11 and CYP4F2, which oxidize both endobiotic and xenobiotic substrates, and contribute to lipid homeostasis, protection from xenobiotics, and signal transduction pathways regulating hemodynamics and inflammation. Although the regulation of CYP4 gene expression has been characterized in various non-human species, significant differences are evident between mammalian species in the number of CYP4 genes and the pathways that govern their expression. The proposed studies address mechanisms of human CYP4F2 gene regulation through the identification of cis-acting control elements and the associated transcription factors that regulate expression of CYP4F2 in response to xenobiotics, hormones and nutritional status. The current proposal focuses on the role of the AMP activated protein kinase and sterol regulatory element binding proteins in this process. CYP4F2 transgenic mice will be generated and used together with CYP4A11 transgenic mice to characterize regulatory responses to xenobiotics and to physiologic alterations that accompany conditions such as nutritional status and inflammation. The CYP4A11 and CYP4F2 transgenes will be expressed in Cyp4a10 null mice to gauge the effect of expression of each transgene on the susceptibility of the Cyp4a10 null mice to develop salt-sensitive hypertension and to relate these changes to differences in renal and hepatic lipid metabolism, inflammation and gene expression. The underlying mechanisms are likely to contribute to the reported association of genetic variation of the human CYP4A11 and CYP4F2 genes with risks for hypertension and related vascular disorders. These mechanisms are likely to reflect the roles of Cyp4a10, CYP4A11 and CYP4F2 in lipid metabolism with consequent effects on gene regulation that contribute to salt dependent hypertension in mice.
The proposed studies will characterize regulatory pathways that enhance or diminish the body's capacity to metabolize and to eliminate potentially toxic excess amounts of nutrients or foreign chemicals in response to xenobiotics, diet and endocrine status. Additionally, we will address how genetic deficiencies of this capacity affect susceptibility to hypertension due to renal and liver dysfunction.
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