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：
8728198
负责人：
Zheng Dong
金额：
$ 30.81万
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 2016-03-14
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8728198
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 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.

描述（由申请人提供）：顺铂是最常用，最有效的化学疗法药物之一。但是，顺铂的使用与正常组织和器官（尤其是肾脏）的主要副作用有关，导致急性肾脏损伤（AKI）和肾衰竭。我们研究的目的是描述顺铂-Aki的细胞信号传导机制，并确定有效的命名策略。肾小管细胞损伤和死亡以及组织损伤使顺铂蛋白Aki涉及多种因素。最近的研究揭示了顺铂-Aki期间管状损伤中的几个上游信号通路，包括SRC，MAPK，P53和快速的DNA损伤响应。但是，目前尚不清楚如何调节这些途径并整合以导致令人印象深刻的肾脏病理。我们的初步研究证明了PKC4在顺铂-aki中的作用的第一个证据。值得注意的是，尽管抑制PKC4受到抑制作用，但它可以防止顺铂诱导的肾脏损伤，但它增强了顺铂诱导的损伤和多个癌细胞系中的损伤和死亡，也增强了卵巢肿瘤异种移植物的体内。我们假设：1）PKC4是顺铂引起的肾损伤期间细胞信号传导的关键调节剂； 2）顺铂治疗期间的PKC4激活涉及SRC家族激酶，并且在激活后，PKC4可能调节p53和/或MAPK信号通路，从而导致肾小管凋亡。 3）抑制PKC4不仅可以保护肾脏，还可以增强顺铂在肿瘤中的化学疗法作用。我们将通过三个特定目的检验这一假设：1）在顺铂-aki期间体内阐明PKC4激活，并通过使用基因敲除模型来确定其致病作用； 2）描述有助于顺铂-Aki的PKC4信号通路； 3）确定阻塞PKC4是否可以保护肾脏并增强顺铂在肿瘤动物中的抗癌作用。该项目的完成不仅将获得AKI的新机械见解，而且还可能发现基于顺铂的化学疗法期间的新且有效的肾脏保护策略。