PROJ 1: ORGANIC ANION TRANSPORTING POLYPEPTIDES IN NUCLEAR RECEPTOR ACTIVATION

该子项目是利用 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得主要资金， 因此可以在其他CRISP条目中表示。列出的机构是 中心，不一定是研究者的机构。 有机阴离子转运多肽（OATPs）参与各种内生菌和许多药物的吸收、分布和消除。多特异性OATP（即OATP，接受广泛的结构不相关底物），如OATP 1B 1和OATP 1B 3，主要在肝脏中表达，介导多种胆汁酸和外源性物质的摄取。核受体法尼醇X受体（FXR）、孕烷X受体（PXR）和维甲酸X受体a（RXRa）是主要在肝脏和小肠中表达的配体激活转录因子。当被配体如胆汁酸和外源性物质激活时，它们调节参与胆固醇和胆汁酸稳态以及药物代谢的各种酶和转运蛋白的表达。该项目的工作假设是OATP 1B 1和OATP 1B 3介导肝细胞摄取核受体配体，这些OATP的功能障碍将影响核受体活化。在具体目标1中，我们将使用稳定转染的细胞系表征OATP 1B 1和OATP 1B 3相对于核受体配体的底物特异性。在具体目标2中，我们将对OATP 1B 1和OATP 1B 3进行详细的定量构效关系（QSAR）分析，这将使我们能够预测新的OATP底物和/或抑制剂。在具体目标3中，我们将使用基于细胞的报告系统中的选定配体来确定OATP底物对核受体活化的影响。OATP 1B 1和OATP 1B 3的底物特异性的详细表征对于理解OATP的特异性至关重要。此外，这将有助于理解和预测潜在的药物相互作用的核受体配体和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。

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.