Objective Cholestasis, the impairment of bile flow, causes liver damage via accumulation of toxic compounds in the liver and is a common and devastating manifestation of liver disease. Obstetric cholestasis (OC) is a reversible form of cholestasis, associated with major adverse pregnancy outcomes, including prematurity and intrauterine death and is caused by an imbalance in bile homeostasis due to genetic and hormonal factors. Heterozygous maternal mutations in hepato-canalicular transporters and the bile acid receptor FXR are described in a small number of OC cases, indicating complex aetiology. The disease usually presents in the third trimester of pregnancy when reproductive hormone concentrations are high, and resolves after delivery, when oestrogen and progesterone levels return to normal. Furthermore, these patients often present with cholestasis outside pregnancy when taking oral contraceptives, indicating that reproductive hormones have an important role in the pathogenesis of OC. We hypothesise that high concentrations of reproductive hormones impair bile acid homeostasis. In this proposal, we propose to evaluate bile acid homeostasis in wild type and Fxr null mice: (a) following administration of reproductive hormones to ovariectomised mice and (b) during gestation. In order to determine the effect reproductive hormones have on bile homeostasis, in vitro NMR will be used to measure serum, bile, urinary, and faecal levels of bile acids, lipids, sex hormones, and their metabolites. Furthermore, we will investigate the expression of genes that are involved in bile acid synthesis, metabolism, transport and regulation. Following the outcome of the studies of metabolite profiles and gene expression, we will identify the molecular pathways by which oestrogens' and progesterone's influence bile homestasis. We expect that the results of these studies will bring us better understanding of the pathogenesis of cholestasis and OC in particular. Fields of science natural sciencesbiological sciencesbiochemistrybiomoleculeslipidsnatural sciencesbiological sciencesgeneticsmutationmedical and health sciencesclinical medicineobstetricsmedical and health sciencesclinical medicinehepatologymedical and health sciencesbasic medicinephysiologyhomeostasis Programme(s) FP6-MOBILITY - Human resources and Mobility in the specific programme for research, technological development and demonstration "Structuring the European Research Area" under the Sixth Framework Programme 2002-2006 Topic(s) MOBILITY-2.1 - Marie Curie Intra-European Fellowships (EIF) Call for proposal FP6-2004-MOBILITY-5 See other projects for this call Funding Scheme EIF - Marie Curie actions-Intra-European Fellowships Coordinator IMPERIAL COLLEGE OF SCIENCE, TECHNOLOGY AND MEDICINE EU contribution No data Address Exhibition Road, South Kensington LONDON United Kingdom See on map Links Website Opens in new window Total cost No data
