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: 7586890
• 负责人: Lauren M Aleksunes
• 金额: $ 9万
• 依托单位: UNIVERSITY OF KANSAS MEDICAL CENTER
• 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 2009-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7586890
• 关键词: ABCC1 gene; 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 Interactions; 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; Institution; Interdisciplinary Study; International; Kansas; Kidney; Knockout Mice; Knowledge; Laboratories; Lead; Ligase; Liver; Luciferases; Medical center; Mentors; Messenger RNA; Methods; Multidrug Resistance-Associated Proteins; Mus; NAD(P)H dehydrogenase (quinone) 1, human; Nephrology; Normal tissue morphology; Numbers; Organ; Outcomes Research; Oxidative Stress; Pathology; Patients; Personal Satisfaction; Pharmaceutical Preparations; Pharmacogenetics; Phase; Plasma; Predisposition; Prevention; Protein Overexpression; Proteins; Public Health; Publishing; Pump; Purpose; 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; Techniques; Testing; Toxic effect; Training; Transcriptional Activation; Universities; 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; prevent; programs; promoter; repaired; research study; response; technique development; tool; trafficking; transcription factor; tumor

DESCRIPTION (provided by applicant): Cisplatin is an effective antineoplastic drug for the treatment of solid tumors, although its clinical use is often limited because of 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 cisplatin-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 transcription factor Nrf2. During the mentored phase (Specific Aim 1), the P.I. will determine the in vivo contribution of Mrp2 to the renal disposition and toxicity of cisplatin using Mrp2-null mice. Additional activities during the mentored phase will include training on a number of techniques that are required for completion of Specific Aims 2 and 3 during the independent award phase. In Specific Aim 2, the P.I. 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, the P.I. will determine the role of Nrf2 in the compensatory induction of Mrp2 during cisplatin injury using Nrf2-null mice and in vitro ChIP assays. The work proposed in this grant will serve as the foundation for transition into an independent investigator at an academic research institution in the next two years. The mentored phase (K99) will occur at the University of Kansas Medical Center under the guidance of Dr. Curtis Klaassen. The proposed studies are expected to reveal the role of Mrp2 in protecting the kidneys from cisplatin toxicity. PUBLIC HEALTH RELRVANCE: Understanding how transporters can protect different organs from chemotherapy-related adverse events will directly impact human health by enabling the development of screening mechanisms that predict drug-drug interactions and detect polymorphisms that increase the susceptibility of patients to toxic side effects. Furthermore, these studies will contribute to our understanding of the adaptive mechanisms that occur within the kidneys in response to drug toxicity.

描述（由申请人提供）： 顺铂是治疗实体瘤的有效抗肿瘤药物，但由于对肾功能的不良影响，其临床应用往往受到限制。这种副作用通常会延迟或妨碍后续的化疗周期，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Mrp2的小鼠对顺铂肾毒性的敏感性增加。此外，Mrp2 在顺铂治疗的野生型小鼠的肾脏中被诱导，可能是作为一种补偿机制，以增强后续化疗周期的清除率。本提案中的实验将检验 Mrp2 对于顺铂的处置和预防顺铂肾毒性至关重要的假设。此外，假设Mrp2的诱导型表达受到转录因子Nrf2的调节。在指导阶段（具体目标 1），P.I.将使用Mrp2缺失小鼠确定Mrp2对顺铂的肾脏处置和毒性的体内贡献。指导阶段的其他活动将包括在独立授予阶段完成具体目标 2 和 3 所需的多种技术培训。在具体目标 2 中，P.I.将使用体外过表达系统确定人 MRP2 中的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，P.I.将使用 Nrf2 缺失小鼠和体外 ChIP 测定确定 Nrf2 在顺铂损伤期间代偿性诱导 Mrp2 中的作用。这笔赠款中提出的工作将成为未来两年内过渡为学术研究机构独立研究员的基础。指导阶段 (K99) 将在 Curtis Klaassen 博士的指导下在堪萨斯大学医学中心进行。拟议的研究有望揭示 Mrp2 在保护肾脏免受顺铂毒性方面的作用。 公共健康相关性：了解转运蛋白如何保护不同器官免受化疗相关不良事件的影响，将能够开发预测药物相互作用和检测增加患者对毒副作用敏感性的多态性的筛选机制，从而直接影响人类健康。此外，这些研究将有助于我们了解肾脏内响应药物毒性的适应性机制。