Xenobiotic Transporter Regulation and IRIP Function

异生物质转运蛋白调节和 IRIP 功能

• 批准号: 9096182
• 负责人: Yan Shu
• 金额: $ 31.52万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-01 至 2018-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9096182
• 关键词: Accounting; Adverse drug effect; Affect; Carrier Proteins; Cell Line; Cell model; Cells; Cellular Membrane; Clinical; Data; Dose; Drug Prescriptions; Drug Regulations; Endotoxemia; Endotoxins; Exons; Fatty Liver; Gene Delivery; Gene Targeting; Genes; Genetic Models; Hepatic; Hepatocyte; In Vitro; Ischemia; Kinetics; Knock-in Mouse; Knockout Mice; Leptin; Lipopolysaccharides; Liver; Liver diseases; Mediating; Membrane; Metabolic; Metformin; Modeling; Molecular; Mouse Protein; Mouse Strains; Mus; Obese Mice; Obesity; Organic Cation Transporter 1; Outcome; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacotherapy; Play; Protein Overexpression; Proteins; Regulation; Reperfusion Injury; Reperfusion Therapy; Research; Role; Site; System; Techniques; Testing; Tissues; Transmembrane Transport; United States; Variant; Wild Type Mouse; Xenobiotics; clinically significant; diabetic; drug efficacy; genetic manipulation; in vivo; liver ischemia; novel; overexpression; prevent; protein expression; protein function; protein transport; response; trafficking; treatment response; uptake

DESCRIPTION (provided by applicant): Xenobiotic transporters play a critical role in drug disposition and response. Among recognized examples, the organic cation transporter 1 (OCT1) has been demonstrated by us as a key determinant of the therapeutic response to metformin, one of top ten prescription drugs in the United States. Despite their clinical significance, many xenobiotic transporters, particularly those uptake transporters including OCT1, are poorly characterized in their regulation. The recently identified ischemia/reperfusion-inducible protein (IRIP) regulates a variety of transporters in vitro mediating membrane transport of endogenous metabolites and xenobiotics. Therefore, IRIP may represent a novel regulatory mechanism for transporter activity with a substantial effect on clinical drug therapy, and studies are highly warranted to characterize the, as of yet unknown, IRIP function in the body. Our exciting preliminary results indicate that hepatic overexpression of IRIP is associated with a strikingly reduced hepatic accumulation of metformin in the mice administrated with the drug. We also observed altered metformin accumulation and IRIP expression in the livers of obese mice and those received the endotoxin lipopolysaccharide (LPS). Using gene targeting, we have generated a knockin mouse strain that can be used to generate global and conditional IRIP knockout mice. These knockout mice, along with our established cell models and gene delivery techniques, provide a powerful system to test our central hypothesis that IRIP expression affects the disposition and response of clinically important drugs which are substrates of the xenobiotic transporters regulated by IRIP. We propose three specific research aims. In Aim 1, by using genetic manipulation and model compounds in cell models, we will delineate the mechanism of transporter regulation by IRIP at the protein activity, cellular and molecular levels. In Aim 2, we will determine how liver- specific and ubiquitous alteration in IRIP expression affects transporter function and metformin disposition. Hepatic conditional IRIP knockout (mIRIP?hep) mice, hepatic IRIP overexpression (mIRIP+hep), global IRIP knockout (mIRIP-/-), and their corresponding control mice will be employed to perform the studies in Aim 2. In addition, as transporter activities and drug disposition are significantly changed during pathophysiological conditions, in Aim 3 we will use the mouse and in vitro cellular models to define the role of IRIP in regulation of drug disposition during fatty liver disease, lipopolysaccharide-induced endotoxemia and ischemia/ reperfusion injury. The proposed research will characterize the first function of mammalian IRIP in the body. The results will significantly aid in our understanding of xenobiotic transporter regulation and provide a target for improvement of drug efficacy and avoidance of drug side effects for patients.

描述（由申请人提供）：异生物质转运蛋白在药物处置和反应中发挥着关键作用。在公认的例子中，我们已证明有机阳离子转运蛋白 1 (OCT1) 是美国十大处方药之一二甲双胍治疗反应的关键决定因素。尽管具有临床意义，但许多异生物质转运蛋白，特别是包括 OCT1 在内的摄取转运蛋白，其调节特征尚不清楚。最近发现的缺血/再灌注诱导蛋白（IRIP）在体外调节多种转运蛋白，介导内源代谢物和外源性物质的膜转运。因此，IRIP 可能代表了一种新型的转运蛋白活性调节机制，对临床药物治疗具有重大影响，并且非常有必要进行研究来表征目前未知的 IRIP 在体内的功能。我们令人兴奋的初步结果表明，在给予该药物的小鼠中，IRIP 的肝脏过度表达与二甲双胍肝脏蓄积的显着减少有关。我们还观察到肥胖小鼠和接受内毒素脂多糖 (LPS) 的小鼠肝脏中二甲双胍蓄积和 IRIP 表达的改变。通过基因打靶，我们培育出了一种敲入小鼠品系，可用于产生全局和条件性 IRIP 敲除小鼠。这些基因敲除小鼠与我们建立的细胞模型和基因递送技术一起，提供了一个强大的系统来测试我们的中心假设，即 IRIP 表达影响临床重要药物的处置和反应，这些药物是 IRIP 调节的外源转运蛋白的底物。我们提出了三个具体的研究目标。在目标1中，通过在细胞模型中使用基因操作和模型化合物，我们将在蛋白质活性、细胞和分子水平上描述IRIP对转运蛋白的调节机制。 在目标 2 中，我们将确定肝脏特异性和普遍存在的 IRIP 表达改变如何影响转运蛋白功能和二甲双胍处置。肝脏条件性 IRIP 敲除 (mIRIP?hep) 小鼠、肝脏 IRIP 过表达 (mIRIP+hep)、整体 IRIP 敲除 (mIRIP-/-) 及其相应的对照小鼠将用于进行目标 2 中的研究。转运蛋白活性和药物分布在病理生理条件下发生显着变化，在目标 3 中，我们将使用小鼠和体外细胞模型来定义 IRIP 在调节中的作用脂肪肝疾病、脂多糖诱导的内毒素血症和缺血/再灌注损伤期间的药物处置。拟议的研究将描述哺乳动物 IRIP 在体内的第一个功能。这些结果将极大地帮助我们了解异生物质转运蛋白的调节，并为提高药物疗效和避免患者药物副作用提供目标。

项目成果

Pharmacological modulation of cytotoxicity and cellular uptake of anti-cancer drugs by PDE5 inhibitors in lung cancer cells.

PDE5 抑制剂对肺癌细胞中抗癌药物的细胞毒性和细胞摄取的药理学调节。

• 发表时间: 2014-01
• 影响因子: 3.7
• 作者: Li, Qing;Shu, Yan
• 通讯作者: Shu, Yan

Multidrug and toxin extrusion proteins mediate cellular transport of cadmium.

多药和毒素挤出蛋白介导镉的细胞转运。

• 发表时间: 2017-01-01
• 影响因子: 3.8
• 作者: Yang, Hong;Guo, Dong;Obianom, Obinna N;Su, Tong;Polli, James E;Shu, Yan
• 通讯作者: Shu, Yan

Ischemia/Reperfusion-Inducible Protein Modulates the Function of Organic Cation Transporter 1 and Multidrug and Toxin Extrusion 1.

缺血/再灌注诱导蛋白调节有机阳离子转运蛋白 1 和多药物和毒素排出 1 的功能。

• 发表时间: 2013-06-03
• 影响因子: 4.9
• 作者: Li, Qing;Yang, Hyekyung;Peng, Xiujuan;Guo, Dong;Dong, Zhongqi;Polli, James E;Shu, Yan
• 通讯作者: Shu, Yan

Transcriptional Regulation of Solute Carrier (SLC) Drug Transporters.

溶质载体（SLC）药物转运蛋白的转录调控。

• 发表时间: 2022-05-29
• 作者: Zhou, Shiwei;Shu, Yan
• 通讯作者: Shu, Yan

Polymorphism of ORM1 is associated with the pharmacokinetics of telmisartan.

ORM1 的多态性与替米沙坦的药代动力学相关。

• 发表时间: 2013
• 影响因子: 3.7
• 作者: Chen, Wang;Shu, Yan;Li, Qing;Xu, Lin;Roederer, Mary W;Fan, Lan;Wu, Lan;He, Fa;Luo, Jian;Tan, Zhi;He, Yi;Zhou, Hong;Chen, Xiang;Zhang, Wei
• 通讯作者: Zhang, Wei