The goal of my proposed research is to investigate the role of cytochrome P450 3A (CYP3A) enzymes in the regulation of blood pressure. This project stems from previous associations of CYP3A activity with certain hypertensive states in model animals and in humans. I thus propose to study the response of blood pressure in mouse models and of reporter genes in cell cultures to manipulations of endogenous and transgenic CYP3A enzymes. I hypothesize that increased CYP3A activity will result in increased blood pressure and alterations in electrolyte balance that include an increase in sodium retention. I will measure the effects of genetic manipulations with tail cuff sphygmomanometry and telemetry. As the CYP3As are also drug metabolizing enzymes, the models that I generate may also be useful for pharmacology studies by other investigators. The major potential benefit conferred by my research would be the identification of a polymorphic and potentially modifiable target with major effects upon the control of human blood pressure and the risk of cardiovascular disease death. ? ?
