Trafficking and Regulation of Drug/Xenobiotic Transporter OAT

药物/异生物质转运蛋白 OAT 的贩运和监管

• 批准号: 8096535
• 负责人: GUOFENG YOU
• 金额: $ 26.49万
• 依托单位: RUTGERS, THE STATE UNIV OF N.J.
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-01 至 2014-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8096535
• 关键词: Acute; Acute Kidney Failure; Adrenergic Agonists; Affect; Angiotensin II; Anti-Inflammatory Agents; Anti-inflammatory; Antibiotics; Antihypertensive Agents; Back; Bilateral; Biochemistry; Bradykinin; Brain; Caveolae; Caveolins; Cell membrane; Cell surface; Cells; Clathrin; Clinical; Coupled; Cultured Cells; Data; Disease; Dominant-Negative Mutation; Down-Regulation; Drug Regulations; Drug Transport; Endosomes; Excretory function; Family; Fluorescence Microscopy; Functional disorder; Future; Goals; HIV; Health; Hepatic; Homeostasis; Hormones; Kidney; Kinetics; Label; Liver; Lysosomes; Mediating; Membrane Protein Traffic; Membrane Proteins; Molecular; Molecular Biology; Neurologic; Organ; Organic Anion Transporters; Parathyroid gland; Pathway interactions; Pharmaceutical Preparations; Physiological; Placenta; Play; Protein Kinase C; Proximal Kidney Tubules; RNA Interference; Rattus; Recycling; Regulation; Role; Signal Pathway; Site-Directed Mutagenesis; Slice; Sorting - Cell Movement; Stimulus; Structure; Syndrome; Testing; Therapeutic; Time; Tissues; Toxic Environmental Substances; Toxic effect; Toxin; Treatment Efficacy; Ureteral obstruction; Xenobiotics; absorption; antitumor drug; base; cell growth regulation; design; fetal; insight; mutant; novel; peptide hormone; response; trafficking

DESCRIPTION (provided by applicant): The organic anion transporter (OAT) family mediates the absorption, distribution, and excretion of a diverse array of environmental toxins, and clinically important drugs, including anti-HIV therapeutics, anti-tumor drugs, antibiotics, anti-hypertensives, and anti- inflammatories, and therefore is critical for the survival of mammalian species. Six OATs have been identified (OAT1, OAT2, OAT3, OAT4, OAT5, and OAT6) and their expression detected in kidney, liver, brain and placenta. OAT dysfunction in these organs significantly contributes to the renal, hepatic, neurological and fetal toxicity and disease. Our long-term goal is to define the molecular mechanisms underlying drug/toxin disposition through OATs. We have strong preliminary data to show that OATs are subjected to acute regulation by cellular signaling pathways and that such regulation is coupled to dynamic changes in OAT cell-surface presentation, suggesting that membrane trafficking is fundamental to transporter homeostasis and regulation. However, the mechanisms underlying this regulation are completely unknown. The major goal of this application is to determine the cellular and molecular mechanisms governing OAT1 trafficking, and to evaluate the physiological and pathophysiological relevance of this form of regulation. Four Specific Aims (SAs) are outlined. In SA-1, we will analyze basal and regulated OAT1 trafficking kinetics. In SA-2, we will dissect the pathways involved in OAT1 trafficking. In SA-3, we will identify the structural motifs in OAT1 sequence involved in their trafficking. In SA-4, we will evaluate the physiological and pathophysiological relevance of OAT1 trafficking in regulation of drug transport activity. Combined approaches of biochemistry and molecular biology will be employed for the proposed studies in tissue slices, and cultured cells. Understanding the trafficking and 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. PUBLIC HEALTH RELEVANCE: The organic anion transporter (OAT) family mediates the absorption, distribution, and excretion of a diverse array of environmental toxins, and clinically important drugs, including anti-HIV therapeutics, anti-tumor drugs, antibiotics, anti-hypertensives, and anti- inflammatories, and therefore is critical for the survival of mammalian species. Six OATs have been identified (OAT1, OAT2, OAT3, OAT4, OAT5, and OAT6) and their expression detected in kidney, liver, brain and placenta. OAT dysfunction in these organs significantly contributes to the renal, hepatic, neurological and fetal toxicity and disease. Our long-term goal is to define the molecular mechanisms underlying drug/toxin disposition through OATs. We have strong preliminary data to show that OATs are subjected to acute regulation by cellular signaling pathways and that such regulation is coupled to dynamic changes in OAT cell-surface presentation, suggesting that membrane trafficking is fundamental to transporter homeostasis and regulation. However, the mechanisms underlying this regulation are completely unknown. The major goal of this application is to determine the cellular and molecular mechanisms governing OAT1 trafficking, and to evaluate the physiological and pathophysiological relevance of this form of regulation. Understanding the trafficking and 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）家族介导了多种环境毒素的吸收，分布和排泄物，以及临床上重要的药物，包括抗HIV疗法，抗肿瘤药物，抗肿瘤药物，抗生素，抗激素，抗激素和抗抗菌症和抗症状的症状至关重要。已经鉴定出六只燕麦（OAT1，OAT2，OAT3，OAT4，OAT5和OAT6），并在肾脏，肝脏，脑和胎盘中检测到它们的表达。这些器官中的燕麦功能障碍显着导致肾脏，肝，神经和胎儿毒性和疾病。我们的长期目标是定义通过燕麦处置药物/毒素处置的分子机制。我们有强大的初步数据，可以表明燕麦受细胞信号通路进行急性调节，并且这种调节与燕麦细胞表面表现的动态变化耦合，这表明膜运输是转运蛋白稳态和调节的基础。但是，该法规的基础机制是完全未知的。该应用的主要目的是确定有关OAT1运输的细胞和分子机制，并评估这种调节形式的生理和病理生理学相关性。概述了四个具体目标（SAS）。在SA-1中，我们将分析基础和监管的OAT1运输动力学。在SA-2中，我们将剖析OAT1贩运所涉及的途径。在SA-3中，我们将确定OAT1序列中涉及的贩运的结构基序。在SA-4中，我们将评估OAT1运输在药物转运活性调节中的生理和病理生理学相关性。在组织切片和培养细胞中，将采用生物化学和分子生物学的结合方法。了解燕麦的贩运和调节是在药物运输领域的一种新颖的重点，将对旨在最大化治疗功效和最大程度减少毒性的策略的未来设计产生重大影响，并将允许对分子，细胞和临床基础的肾，肝，神经和胎儿毒性和疾病的临床基础。公共卫生相关性：有机阴离子转运蛋白（OAT）家族介导了多种环境毒素的吸收，分布和排泄物，以及临床上重要的药物，包括抗HIV治疗学，抗肿瘤药物，抗肿瘤药物，抗生素，抗激素敏感性和抗炎性药物和​​抗炎性症和抗炎性症和抗炎性症的生存是至关重要的。已经鉴定出六只燕麦（OAT1，OAT2，OAT3，OAT4，OAT5和OAT6），并在肾脏，肝脏，脑和胎盘中检测到它们的表达。这些器官中的燕麦功能障碍显着导致肾脏，肝，神经和胎儿毒性和疾病。我们的长期目标是定义通过燕麦处置药物/毒素处置的分子机制。我们有强大的初步数据，可以表明燕麦受细胞信号通路进行急性调节，并且这种调节与燕麦细胞表面表现的动态变化耦合，这表明膜运输是转运蛋白稳态和调节的基础。但是，该法规的基础机制是完全未知的。该应用的主要目的是确定有关OAT1运输的细胞和分子机制，并评估这种调节形式的生理和病理生理学相关性。了解燕麦的贩运和调节是在药物运输领域的一种新颖的重点，将对旨在最大化治疗功效和最大程度减少毒性的策略的未来设计产生重大影响，并将允许对分子，细胞和临床基础的肾，肝，神经和胎儿毒性和疾病的临床基础。