Protective Role of Mrp2 During Chemotherapy-Induced Kidney Injury

Mrp2 在化疗引起的肾损伤中的保护作用

• 批准号: 8140530
• 负责人: Lauren M Aleksunes
• 金额: $ 23.08万
• 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: 2008-09-25 至 2013-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8140530
• 关键词: Accounting; Adverse drug effect; Adverse effects; Adverse event; Algorithms; Analytical Chemistry; Antineoplastic Agents; Apical; Applications Grants; Award; Binding; Biochemical; Biological Assay; Brush Border; Carrier Proteins; Cell Line; Cell Survival; Cells; Chemicals; Cisplatin; Clinical; Code; Core Facility; Cysteine; Cytotoxic agent; Data; Databases; Development; Dose; Drug Kinetics; Drug Metabolic Detoxication; Drug toxicity; Elements; Embryo; Enzymes; Equipment; Excretory function; Foundations; Gene Targeting; Generations; Genes; Genetic Polymorphism; Goals; Grant; Health; Histology; Human; In Vitro; Individual; Injury; Instruction; Interdisciplinary Study; International; Kidney; Knockout Mice; Knowledge; Laboratories; Lead; Ligase; Liver; Luciferases; Mentors; Messenger RNA; Methods; Multidrug Resistance-Associated Proteins; Mus; NAD(P)H dehydrogenase (quinone) 1, human; Nephrology; Normal tissue morphology; Organ; Outcome; Oxidative Stress; Pathology; Patients; Pharmaceutical Preparations; Pharmacogenetics; Pharmacologic Substance; Phase; Plasma; Predisposition; Prevention; Proteins; Publishing; Pump; Recovery; Regulation; Renal Tissue; Renal clearance function; Renal function; Renal tubule structure; Research; Research Personnel; Resistance; Response Elements; Risk; Rodent; Role; Screening procedure; Signal Pathway; Single Nucleotide Polymorphism; Solid Neoplasm; Surface; SwissProt; System; Testing; Toxic effect; Training; Up-Regulation; Urine; Variant; Wild Type Mouse; Work; Xenobiotics; adduct; base; cancer cell; chemotherapeutic agent; chemotherapy; chromatin immunoprecipitation; cytotoxicity; experience; gene therapy; heme oxygenase-1; in vivo; in vivo Model; innovation; insight; kidney cell; neoplastic cell; nephrotoxicity; novel; overexpression; prevent; promoter; repaired; research study; response; technique development; tool; trafficking; transcription factor; tumor

PROJECT SUMMARY (See instructions): Cisplatin is an effective antineoplastic drug for the treatment of solid tumors, although its clinical use can be limited by adverse effects on renal function. This side effect often delays or precludes subsequent chemotherapy cycles, thereby reducing the overall antineoplastic efficacy of cisplatin, Preliminary data demonstrate that mice lacking the renal drug transporter Mrp2 have an increased susceptibility to cisplatin nephrotoxicity. In addition, Mrp2 is Induced in the kidneys of cisplatln-treated wild-type mice likely as a compensatory mechanism to enhance clearance of subsequent chemotherapy cycles. Experiments in this proposal will test the hypothesis that Mrp2 is critical for the disposition of cisplatin and prevention of cisplatin nephrotoxicity. Furthermore, it is hypothesized that the inducible expression of Mrp2 is regulated by the oxidative stress-responsive transcription factor Nrf2. In Specific Aim 1, we will determine the in vivo contribution of Mrp2 to the renal disposition and toxicity of cisplatin using Mrp2-null mice. In Specific Aim 2, we will establish which single nucleotide polymorphisms in human MRP2 influence transport of cisplatin conjugates and cisplatin cytotoxicity using an in vitro overexpression system. In Specific Aim 3, we will determine the role of Nrf2 in the compensatory induction of Mrp2 during cisplatin injury using Nrf2-null mice and in vitro ChlP assays. The work proposed in this grant serves as the independent portion of the K99/R00 grant. The proposed studies are expected to reveal the role of Mrp2 transport In protecting the kidneys from cisplatin toxicity.

项目总结（见说明）： 顺铂是一种有效的治疗实体瘤的化疗药物，尽管其临床应用可能受到限制。 受肾功能不良影响的限制。这种副作用通常会延迟或阻止随后的 化疗周期，从而降低顺铂的总体抗肿瘤功效。初步数据表明，缺乏肾脏药物转运蛋白Mrp 2的小鼠对顺铂肾毒性的易感性增加。此外，Mrp 2在顺铂处理的野生型小鼠的肾脏中被诱导，可能是一种补偿机制，以提高随后化疗周期的清除率。本提案中的实验将检验Mrp 2对顺铂的处置和预防顺铂肾毒性至关重要的假设。此外，据推测，Mrp 2的诱导型表达受氧化应激反应转录因子Nrf 2的调节。在具体目标1中，我们将使用Mrp 2缺失小鼠确定Mrp 2对顺铂的肾处置和毒性的体内贡献。在特定目标2中，我们将使用体外过表达系统确定人MRP 2中哪些单核苷酸多态性影响顺铂缀合物的转运和顺铂细胞毒性。在具体目标3中，我们将使用Nrf 2缺失小鼠和体外ChlP测定来确定Nrf 2在顺铂损伤期间Mrp 2的代偿诱导中的作用。本补助金中提出的工作作为K99/R 00的独立部分 格兰特.预计拟议的研究将揭示Mrp 2转运在保护肾脏免受顺铂毒性中的作用。