This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Nuclear receptor constitutive androstane/active receptor (CAR) has been implicated as a central regulator for drug metabolism in the liver. My long-term goal is to understand the molecular mechanism by which the hepatic drug metabolism genes are regulated, with the purpose to improve drug efficacy and safety in humans. The objective of this application is to reveal the in vivo epigenetic regulatory mechanism of human CAR (hCAR) expression during development. I have engineered a line of hCAR bacteria artificial chromosome (BAC) transgenic mice and demonstrated that the transgenic mice express functional hCAR protein and various splicing variants of hCAR mRNA in liver with a series of preliminary experiments. My proposed studies will (Aim1) further validate the hCAR BAC-transgenic mice as an in vivo model to study epigenetic regulation of the hCAR gene, and (Aim 2) determine the epigenetic factors that regulate the expression level and alternative splicing of hCAR mRNA in liver during development. The completion of this proposal will provide fundamental information for the molecular regulation of hCAR at various developmental stages, which is important for drug administration to children of different ages. This research will form the basis for a continuum of research on the systematic regulatory mechanisms of human CAR, which is to be proposed in an R01 grant application in February, 2012.
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