Acute Kidney Injury by Cisplatin and Renoprotective Strategies

顺铂引起的急性肾损伤和肾脏保护策略

基本信息

批准号：
8530225
负责人：
Zheng Dong
金额：
$ 29.74万
依托单位：
AUGUSTA UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-09-30 至 2015-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8530225
关键词：
Acute Acute Renal Failure with Renal Papillary Necrosis Adverse effects Animal Model Animals Apoptosis C57BL/6 Mouse Cancer Biology Cancer Patient Cancer cell line Cell Death Cells Cessation of life Chronic Cisplatin Colonic Neoplasms DNA Damage Diuresis Foundations Genotype Goals Hydration status In Vitro Injury Kidney Kidney Failure Knockout Mice MAP Kinase Gene MAPK Signaling Pathway Pathway Malignant Neoplasms Malignant neoplasm of ovary Modeling Normal tissue morphology Organ Pathology Pathway interactions Patients Pharmaceutical Preparations Physiology Platinum Compounds Publishing Regulation Research Role Signal Pathway Signal Transduction Testicular Neoplasms Testing Therapeutic Tissues Tubular formation Work Xenograft Model base cancer cell cancer therapy cell injury chemotherapy clinically relevant in vivo inhibitor/antagonist insight kidney cell knockout gene nephrotoxicity novel ovarian neoplasm public health relevance response rottlerin src-Family Kinases tumor tumor xenograft

项目摘要

DESCRIPTION (provided by applicant): Cisplatin is one of the most widely used and most potent chemotherapy drugs. However, the use of cisplatin is associated with major side effects in normal tissues and organs, especially the kidneys, leading to acute kidney injury (AKI) and renal failure. The goal of our research is to delineate the cell signaling mechanism of cisplatin-AKI and identify effective strategies for renoprotection. Cisplatin-AKI, involving multiple factors, is nevertheless precipitated by renal tubular cell injury and death, and tissue damage. Recent research has revealed several upstream signaling pathways in tubular damage during cisplatin-AKI, including Src, MAPK, p53 and a rapid DNA damage response. However, it remains unclear how these pathways are regulated and integrated to result in an impressive renal pathology. Our preliminary studies demonstrated the first evidence for a role of PKC4 in cisplatin-AKI. Notably, while inhibition of PKC4 protected against cisplatin-induced kidney injury, it enhanced cisplatin-induced injury and death in multiple cancer cells lines and also in vivo in ovarian tumor xenografts. We hypothesize that: 1) PKC4 is a key regulator of cell signaling during cisplatin-induced kidney injury; 2) PKC4 activation during cisplatin treatment involves a Src family kinase and after being activated, PKC4 may regulate p53 and/or MAPK signaling pathways to result in renal tubular apoptosis; and 3) inhibition of PKC4 not only protects kidneys but can also enhance the chemotherapy effects of cisplatin in tumors. We will test this hypothesis by three Specific Aims: 1) elucidate PKC4 activation in vivo during cisplatin-AKI and establish its pathogenic role by using gene knockout models; 2) delineate the PKC4 signaling pathway that contributes to cisplatin-AKI; and 3) determine if blocking PKC4 can protect kidneys and enhance the anti-cancer effect of cisplatin in tumor-bearing animals. Completion of the project will not only gain novel mechanistic insights of AKI but may also discover a new and effective strategy for renoprotection during cisplatin-based chemotherapy. PUBLIC HEALTH RELEVANCE: Over a quarter of patients receiving cisplatin-based chemotherapy develop renal problems, leading to acute kidney injury and renal failure. No effective approaches are currently available to protect the kidneys in these cancer patients. By revealing a new signaling mechanism of cisplatin injury, this project will significantly advance the understanding of acute kidney injury associated with cisplatin chemotherapy. Moreover, it may discover a clinically applicable strategy for renoprotection that not only protects kidneys but may also enhance the chemotherapy effects of cisplatin in tumors.

描述（由申请人提供）：顺铂是最广泛使用和最有效的化疗药物之一。然而，顺铂的使用会对正常组织和器官（尤其是肾脏）产生严重副作用，导致急性肾损伤（AKI）和肾衰竭。我们研究的目标是阐明顺铂-AKI 的细胞信号传导机制并确定有效的肾脏保护策略。然而，顺铂-AKI涉及多种因素，是由肾小管细胞损伤和死亡以及组织损伤引发的。最近的研究揭示了顺铂 AKI 期间肾小管损伤的几个上游信号通路，包括 Src、MAPK、p53 和快速 DNA 损伤反应。然而，目前尚不清楚这些途径是如何调节和整合以产生令人印象深刻的肾脏病理学的。我们的初步研究首次证明了 PKC4 在顺铂 AKI 中的作用。值得注意的是，虽然抑制 PKC4 可以防止顺铂诱导的肾损伤，但它在多种癌细胞系以及体内卵巢肿瘤异种移植物中增强了顺铂诱导的损伤和死亡。我们假设：1）PKC4 是顺铂诱导的肾损伤过程中细胞信号传导的关键调节因子； 2）顺铂治疗过程中PKC4的激活涉及Src家族激酶，PKC4被激活后可能调节p53和/或MAPK信号通路导致肾小管凋亡； 3）抑制PKC4不仅可以保护肾脏，还可以增强顺铂对肿瘤的化疗效果。我们将通过三个具体目标来检验这一假设：1）阐明顺铂-AKI 期间体内 PKC4 的激活，并通过使用基因敲除模型确定其致病作用； 2) 描绘导致顺铂-AKI 的 PKC4 信号通路； 3)确定阻断PKC4是否可以保护肾脏并增强顺铂对荷瘤动物的抗癌作用。该项目的完成不仅将获得对 AKI 的新机制见解，还可能发现顺铂化疗期间新的有效的肾脏保护策略。公众健康相关性：超过四分之一接受顺铂化疗的患者出现肾脏问题，导致急性肾损伤和肾衰竭。目前还没有有效的方法来保护这些癌症患者的肾脏。通过揭示顺铂损伤的新信号机制，该项目将显着增进对顺铂化疗相关急性肾损伤的理解。此外，它可能会发现一种临床适用的肾脏保护策略，不仅可以保护肾脏，还可以增强顺铂在肿瘤中的化疗效果。