PROJ 1: ORGANIC ANION TRANSPORTING POLYPEPTIDES IN NUCLEAR RECEPTOR ACTIVATION

这个子项目是众多研究子项目之一

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Organic Anion Transporting Polypeptides (OATPs) are involved in absorption, distribution, and elimination of various endobiotics and numerous drugs. Multispecific OATPs (i.e. OATPs, which accept a broad range of structurally unrelated substrates) like OATP1B1 and OATP1B3, are predominantly expressed in liver where they mediate uptake of numerous bile acids and xenobiotics. The nuclear receptors farnesoid-X-receptor (FXR), pregnane-X-receptor (PXR) and retinoid-X-receptor a (RXRa) are ligand activated transcription factors expressed mainly in liver and small intestine. When activated by ligands, like bile acids and xenobiotics, they regulate the expression of various enzymes and transporters involved in cholesterol and bile-acid homeostasis, and drug metabolism. The working hypothesis of this project is that OATP1B1 and OATP1B3 mediate hepatocellular uptake of nuclear-receptor ligands, and that malfunction of these OATPs will affect nuclear-receptor activation. In specific aim 1, we will characterize the substrate specificity of OATP1B1 and OATP1B3 with respect to nuclear-receptor ligands using stably transfected cell lines. In specific aim 2, we will perform a detailed quantitative structure activity relationship (QSAR) analysis for OATP1B1 and OATP1B3, which will allow us to predict new OATP substrates and/or inhibitors. In specific aim 3, we will determine the effect of OATP substrates on nuclear-receptor activation using selected ligands in a cell-based reporter system. A detailed characterization of the substrate specificity of OATP1B1 and OATP1B3 is essential for understanding the specificity of OATPs. Furthermore, it will help to understand and predict potential drug-drug interactions of nuclear-receptor ligands and OATP substrates, such as the lipid lowering statins and the antidiabetic glitazones at the transporter level.