Xenobiotic Transporter Regulation and IRIP Function

异生物质转运蛋白调节和 IRIP 功能

• 批准号: 8369927
• 负责人: Yan Shu
• 金额: $ 33.69万
• 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 2017-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8369927
• 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; 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; Therapeutic; Tissues; Transmembrane Transport; United States; Variant; Wild Type Mouse; Xenobiotics; clinically significant; diabetic; drug efficacy; genetic manipulation; in vivo; novel; overexpression; prevent; protein expression; protein function; protein transport; response; trafficking; 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. PUBLIC HEALTH RELEVANCE: Despite their clinical significance, many xenobiotic transporters are poorly understood in their regulation, which significantly prevents from fully understanding the contribution of their functional changes to patient variation in drug response. The proposed studies will determine whether the novel ischemia/reperfusion inducible protein IRIP plays a critical role in the disposition and response of drugs, such as the top prescribed anti-diabetic metformin, via its negative modulation on the activities of xenobiotic transporters. Findings from these studies may greatly aid in our understanding of xenobiotic transporter regulation and have a substantial significance for drug therapy in patients.

描述（由申请人提供）：异生元转运蛋白在药物处置和反应中起关键作用。在公认的例子中，我们证明了有机阳离子转运蛋白1（OCT1）是对二甲双胍的治疗反应的关键决定因素，二甲双胍是美国十种处方药之一。尽管具有临床意义，但许多异生元转运蛋白，尤其是包括OCT1在内的摄取转运蛋白的转运蛋白，其调节的特征很差。最近确定的缺血/再灌注诱导蛋白（IRIP）调节内源性代谢产物和异种生物的膜转运的各种转运蛋白。因此，IRIP可以代表一种用于转运蛋白活性的新型调节机制，对临床药物治疗具有重大影响，并且高度保证研究表征体内IRIP功能。我们令人兴奋的初步结果表明，IRIP的肝过表达与用该药物管理的小鼠中二甲双胍的肝积累大幅降低有关。我们还观察到肥胖小鼠肝脏中的二甲双胍积累和IRIP表达改变，而接受内毒素脂多糖（LPS）。使用基因靶向，我们产生了一种可用于生成全球和有条件的IRIP敲除小鼠的敲除小鼠菌株。这些敲除小鼠以及我们既定的细胞模型和基因输送技术，提供了一个强大的系统，可以测试我们的中心假设，即IRIP表达会影响临床上重要的药物的处置和反应，这些药物是由IRIP调节的异生物生物转运蛋白的底物。我们提出了三个特定的研究目的。在AIM 1中，通过在细胞模型中使用遗传操作和模型化合物，我们将在蛋白质活性，细胞和分子水平上通过IRIP来描述转运蛋白调节的机理。 在AIM 2中，我们将确定IRIP表达中肝脏特异性和普遍存在的变化如何影响转运蛋白功能和二甲双胍的处置。肝条件IRIP敲除（mirip？hep）小鼠，肝IRIP过表达（miRIP+HEP），全球IRIP敲除（mirip-/ - ）及其相应的对照小鼠将在AIM 2中进行研究。此外，由于在病理学状态下，在AIM中，在AIM中，在AIM中会显着改变AIM和药物处于AIM中的范围，我们将在AIM中进行辩护。脂肪肝疾病，脂多糖引起的内毒素血症和缺血/再灌注损伤期间的药物处置。拟议的研究将表征体内哺乳动物IRIP的第一个功能。结果将大大有助于我们对异生物生物转运蛋白调节的理解，并为提高药物疗效和避免药物副作用的目标提供了一个目标。 公共卫生相关性：尽管具有临床意义，但许多异种生物转运蛋白的调节却很少了解，这极大地阻止了其功能变化对患者对药物反应变化的贡献。拟议的研究将通过对异种生物传播蛋白的负面调节来确定新型缺血/再灌注诱导蛋白IRIP是否在药物的处置和反应中起着至关重要的作用，例如最高处方的抗糖尿病二甲双胍。这些研究的发现可能大大有助于我们理解异生物生物转运蛋白调节，并且对患者的药物治疗具有重要意义。