PROJ 1: ORGANIC ANION TRANSPORTING POLYPEPTIDES IN NUCLEAR RECEPTOR ACTIVATION

本子项目是利用由NIH/NCRR资助的中心赠款提供的资源的众多研究子项目之一。子项目和研究者（PI）可能已经从另一个NIH来源获得了主要资金，因此可以在其他CRISP条目中表示。列出的机构是中心的，不一定是研究者的机构。有机阴离子转运多肽（oats）参与多种内源性药物和多种药物的吸收、分布和消除。多特异性oatp（即接受广泛的结构无关底物的oatp），如OATP1B1和OATP1B3，主要在肝脏中表达，介导多种胆汁酸和外源药物的摄取。核受体farnesoids - x -receptor （FXR）、pregnan - x -receptor （PXR）和retinoids - x -receptor a （RXRa）是配体激活的转录因子，主要表达于肝脏和小肠。当被配体激活时，如胆汁酸和外源生物，它们调节各种酶和转运体的表达，这些酶和转运体参与胆固醇和胆汁酸的稳态和药物代谢。本项目的工作假设是OATP1B1和OATP1B3介导肝细胞对核受体配体的摄取，而这些oatp的功能障碍会影响核受体的激活。在特定目标1中，我们将使用稳定转染的细胞系来表征OATP1B1和OATP1B3对核受体配体的底物特异性。在具体目标2中，我们将对OATP1B1和OATP1B3进行详细的定量结构活性关系（QSAR）分析，这将使我们能够预测新的OATP底物和/或抑制剂。在特定目标3中，我们将在基于细胞的报告系统中使用选择的配体确定OATP底物对核受体激活的影响。详细表征OATP1B1和OATP1B3的底物特异性对于理解oatp的特异性至关重要。此外，它将有助于了解和预测核受体配体和OATP底物（如降脂他汀类药物和抗糖尿病格列酮）在转运蛋白水平上的潜在药物-药物相互作用。

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.