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Regulation of Drug/Xenobiotic Transporter OAT by Ubiquitination

泛素化对药物/异生物质转运蛋白 OAT 的调节

基本信息

批准号：
8811974
负责人：
GUOFENG YOU
金额：
$ 29万
依托单位：
RUTGERS, THE STATE UNIV OF N.J.
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-06-07 至 2017-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8811974
关键词：
Acute Kidney Failure Amino Acids Angiotensin II Animals Anti-Inflammatory Agents Anti-inflammatory Antibiotics Antibodies Antihypertensive Agents Bilateral Biochemistry Brain Cell surface Clinical Cultured Cells Data Disease Drug Regulations Drug Transport Endocytosis Excretory function Family Functional disorder Future Goals HIV Hepatic Immunoblotting Kidney Liver Mediating Membrane Proteins Molecular Molecular Biology Mono-S Nature Neurologic Organ Organic Anion Transporters Outcome Pharmaceutical Preparations Physiological Placenta Play Polyubiquitin Polyubiquitination Post-Translational Protein Processing Process Protein Kinase C Proteins Rattus Regulation Role Site-Directed Mutagenesis Slice Sorting - Cell Movement Surface Syndrome Therapeutic Tissues Toxic Environmental Substances Toxic effect Treatment Efficacy Ubiquitin Ubiquitination Ureteral obstruction Ursidae Family Xenobiotics absorption antitumor drug base design fetal in vivo insight novel

项目摘要

DESCRIPTION (provided by applicant): Organic anion transporters (OATs) mediate the absorption, distribution, and excretion of clinically important drugs, including anti-HIV therapeutics, anti-tumor drugs, antibiotics, anti-hypertensives, and anti-inflammatories. OATs are mainly expressed in kidney, liver, brain and placenta. OAT dysfunction in these organs significantly contributes to the renal, hepatic, neurological and fetal toxicity and disease. We have novel preliminary data to show that the surface expression and activity of OAT3 are controlled by the ubiquitination of the transporter. The goal of this application is to determine the cellular and molecular mechanisms governing the regulation of OAT3 activity by ubiquitination, and to evaluate the physiological and pathophysiological relevance of such regulation. Three Specific Aims (SAs) are outlined. In SA-I, we will identify the nature of OAT3 ubiquitination. In SA-II, we will assess the role of ubiquitination in OAT3-mediated drug transport. In SA-III, we will evaluate the physiological and pathophysiological relevance of ubiquitination in OAT3-mediated drug transport. Combined approaches of biochemistry and molecular biology will be employed for the proposed studies in cultured cells, in tissue slices, and in animals. Understanding the role of ubiquitination in the regulation of OATs, a novel focus in drug transport field, will have significant impact on the future design of strategies aimed at maximizing therapeutic efficacy and minimizing toxicity, and will permit insight into the molecular, cellular, and clinical bases of renal, hepatic, neurological and fetal toxicity and disease.

描述（由申请人提供）：有机阴离子转运蛋白（OAT）介导临床重要药物的吸收、分布和排泄，包括抗HIV治疗药物、抗肿瘤药物、抗生素、抗高血压药物和抗炎药。OAT主要在肾脏、肝脏、脑和胎盘中表达。这些器官中的OAT功能障碍显著导致肾、肝、神经和胎儿毒性和疾病。我们有新的初步数据表明，OAT 3的表面表达和活性是由转运蛋白的泛素化控制的。本申请的目的是确定通过泛素化调控OAT 3活性的细胞和分子机制，并评价这种调控的生理和病理生理相关性。三个具体目标（SA）被概述。在SA-I中，我们将确定OAT 3泛素化的性质。在SA-II中，我们将评估泛素化在OAT 3介导的药物转运中的作用。在SA-III中，我们将评估OAT 3介导的药物转运中泛素化的生理和病理生理相关性。生物化学和分子生物学的组合方法将用于培养细胞、组织切片和动物中的拟议研究。了解泛素化在OAT调控中的作用，是药物转运领域的一个新焦点，将对未来设计旨在最大化治疗效果和最小化毒性的策略产生重大影响，并将允许深入了解肾脏，肝脏，神经和胎儿毒性和疾病的分子，细胞和临床基础。