Save Kidneys in Cisplatin Chemotherapy by blocking HDAC6

顺铂化疗中通过阻断 HDAC6 拯救肾脏

• 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
• 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

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.

项目摘要 顺铂及其衍生物是用于治疗实体瘤的最广泛使用的化学治疗剂。 但是，顺铂在癌症治疗中诱导肾脏损伤。目前，没有治疗 除支持护理外，顺铂诱导的急性和慢性肾损伤。该项目的目的是阐明 组蛋白脱乙酰基酶6（HDAC6）在顺铂诱导的肾损伤，纤维化和慢性的作用和机制 肾脏疾病（CKD），并确定HDAC6抑制作用是一种新型的肾脏保护方法。我们的初步 研究表明，单一的高剂量顺铂在中引起的HDAC6在急性肾损伤（AKI）中被上调。 在该模型中，HDAC6的小鼠和药物抑制减弱了肾小管凋亡和AKI。 HDAC6 还可以重复的低剂量顺铂治疗高度诱导，这是通过肾脏间隙完成的 表皮生长因子受体（EGFR）和自噬的纤维化，持续激活以及脱乙酰基化 α-微管蛋白，这是纤毛拆卸的关键过程。此外，顺铂治疗诱导了原发性的缩短 培养的肾上皮细胞中的纤毛，以及较短纤毛的细胞对顺铂诱导的更敏感 凋亡。这些研究提供了初步证据，表明HDAC6可能介导顺铂诱导的肾脏 损坏和潜在机制可能涉及EGFR，自噬和睫状拆卸。这些数据， 加上HDAC6在肿瘤中的已知癌症促进作用的作用，导致了我们的假设 HDAC6可以在顺铂化疗期间保护肾脏，同时提高其在肿瘤中的抗癌效率。 从机械上讲，HDAC6可能通过激活EGFR导致顺铂引起的肾脏问题 和自噬，肾小管细胞中原代纤毛的拆卸。为了检验这些假设，我们将 确定（1）HDAC6的阻断是否可以在顺铂治疗期间保护肾脏 化学疗法对肿瘤的影响； （2）HDAC6是否有助于顺铂诱导的肾损伤，纤维化和 CKD通过EGFR和自噬的持续激活； （3）HDAC6介导的睫状拆卸是否是否 顺铂治疗后，加重肾脏损伤，纤维化和CKD。这个多个PI项目利用了 Shougang Zhuang博士在EGFR信号和表观遗传调节中的完整专业知识和博士 自噬和顺铂肾毒性中的郑博。拟议研究的成功完成将定义 HDAC6抑制对顺铂诱导的肾损伤和纤维化的治疗作用，阐明 潜在的机制，并确定一种新的肾脏保护策略，同时增强化学治疗 功效。