Save Kidneys in Cisplatin Chemotherapy by blocking HDAC6

顺铂化疗中通过阻断 HDAC6 拯救肾脏

基本信息

批准号：
10841270
负责人：
Zheng Dong
金额：
$ 10万
依托单位：
RHODE ISLAND HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-09-01 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10841270
关键词：
Acute Acute Renal Failure with Renal Papillary Necrosis Animals Apoptosis Attenuated Autophagocytosis Cells Chronic Chronic Kidney Failure Cilia Cisplatin Clone Cells Data Deacetylation Dose Epidermal Growth Factor Receptor Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Epithelial Cells Fibrosis Gefitinib Goals HDAC6 gene Histone Deacetylase Histone Deacetylase Inhibitor Induction of Apoptosis Injury to Kidney Kidney Malignant Neoplasms Mediating Modeling Mus Pathology Phenotype Process Receptor Activation Receptor Signaling Renal tubule structure Reporting Research Research Personnel Role Signal Pathway Solid Neoplasm Supportive care Testing Therapeutic Effect Treatment Efficacy Tubular formation alpha Tubulin anti-cancer cancer therapy chemotherapeutic agent chemotherapy epigenetic regulation inhibitor interstitial kidney fibrosis mouse model nephrotoxicity novel strategies pharmacologic renal damage renal epithelium tool tumor

项目摘要

Project Summary Cisplatin and its derivatives are the most widely used chemotherapeutic agents for treating solid tumors. However, cisplatin induces kidney injury during its use in cancer therapy. Currently, no treatment is available for cisplatin-induced acute and chronic kidney injury except supportive care. The goal of this project is to elucidate the role and mechanism of histone deacetylase 6 (HDAC6) in cisplatin-induced kidney injury, fibrosis and chronic kidney disease (CKD), and to identify HDAC6 inhibition as a novel approach for renoprotection. Our preliminary studies show that HDAC6 is up-regulated in acute kidney injury (AKI) induced by a single high-dose of cisplatin in mice and pharmacological inhibition of HDAC6 attenuates renal tubular apoptosis and AKI in this model. HDAC6 is also highly induced by repeated low-dose cisplatin treatment, which is accompanied by renal interstitial fibrosis, persistent activation of epidermal growth factor receptor (EGFR) and autophagy, and deacetylation of α-tubulin, a key process in cilium disassembly. Moreover, cisplatin treatment induces shortening of primary cilium in cultured renal epithelial cells, and the cells with shorter cilia are more sensitive to cisplatin-induced apoptosis. These studies provide preliminary evidence that HDAC6 may mediate cisplatin-induced kidney damage and that the underlying mechanism may involve EGFR, autophagy and ciliary disassembly. These data, together with a known cancer-promoting role of HDAC6 in tumors, have led to our hypothesis that blockade of HDAC6 may protect kidneys during cisplatin chemotherapy while enhancing its anti-cancer efficacy in tumors. Mechanistically, HDAC6 may contribute to cisplatin-induced kidney problems through the activation of EGFR and autophagy, and disassembly of primary cilium in renal tubular cells. To test these hypotheses, we will determine (1) whether blockade of HDAC6 can protect kidneys during cisplatin treatment while enhancing the chemotherapy effects in tumors; (2) whether HDAC6 contributes to cisplatin-induced renal injury, fibrosis and CKD by persistent activation of EGFR and autophagy; and (3) whether HDAC6-mediated ciliary disassembly aggravates kidney injury, fibrosis and CKD following cisplatin treatment. This multiple PI project takes advantage of the complementary expertise of Dr. Shougang Zhuang in EGFR signaling and epigenetic regulation and Dr. Zheng Dong in autophagy and cisplatin nephrotoxicity. Successful completion of the proposed studies will define the therapeutic effect of HDAC6 inhibition on cisplatin-induced renal damage and fibrosis, elucidate the underlying mechanisms, and identify a novel strategy for kidney protection while enhancing chemotherapeutic efficacy.

项目概要顺铂及其衍生物是治疗实体瘤最广泛使用的化疗药物。然而，顺铂在用于癌症治疗期间会引起肾损伤，目前尚无治疗方法。除支持治疗外顺铂引起的急性和慢性肾损伤该项目的目标是阐明。组蛋白脱乙酰酶6（HDAC6）在顺铂诱导的肾损伤、纤维化及慢性肾损伤中的作用及机制肾脏疾病（CKD），并确定 HDAC6 抑制作为肾脏保护的新方法。研究表明，单次大剂量顺铂诱导的急性肾损伤（AKI）中 HDAC6 上调小鼠中 HDAC6 的药理抑制可减轻该模型中的肾小管凋亡和 AKI。反复小剂量顺铂治疗也高度诱发，并伴有肾间质纤维化、表皮生长因子受体 (EGFR) 和自噬的持续激活以及脱乙酰化 α-微管蛋白是纤毛分解的关键过程，而且顺铂治疗会导致初级缩短。培养的肾上皮细胞中存在纤毛，纤毛较短的细胞对顺铂诱导更敏感这些研究提供了 HDAC6 可能介导顺铂诱导的肾细胞凋亡的初步证据。损伤，潜在机制可能涉及 EGFR、自噬和纤毛分解这些数据，加上 HDAC6 在肿瘤中已知的促癌作用，导致我们假设阻断 HDAC6可能在顺铂化疗期间保护肾脏，同时增强其对肿瘤的抗癌功效。从机制上讲，HDAC6 可能通过激活 EGFR 导致顺铂诱发的肾脏问题肾小管细胞中的自噬和初级纤毛的分解为了检验这些假设，我们将确定 (1) 阻断 HDAC6 是否可以在顺铂治疗期间保护肾脏，同时增强化疗对肿瘤的影响；（2）HDAC6是否会导致顺铂诱导的肾损伤、纤维化和 CKD 是由 EGFR 和自噬的持续激活引起的；(3) HDAC6 是否介导纤毛分解；顺铂治疗后会加重肾损伤、纤维化和 CKD，这种多重 PI 项目利用了这一优势。庄守刚博士在 EGFR 信号传导和表观遗传调控方面的专业知识与庄守刚博士的互补专业知识。郑东在自噬和顺铂肾毒性方面的研究将成功完成。 HDAC6 抑制对顺铂诱导的肾损伤和纤维化的治疗作用，阐明潜在机制，并确定一种新的肾脏保护策略，同时增强化疗功效。