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。 然而，顺铂在其用于癌症治疗期间诱导肾损伤。目前，没有治疗方法可用于 顺铂诱导的急性和慢性肾损伤，支持治疗除外。这个项目的目标是阐明 组蛋白脱乙酰酶6（HDAC 6）在顺铂诱导肾损伤、纤维化和慢性肾损伤中的作用及其机制 肾脏疾病（CKD），并确定HDAC 6抑制作为肾保护的新方法。我们的初步 研究表明，HDAC 6在由单次高剂量顺铂诱导的急性肾损伤（阿基）中上调， 在该模型中，HDAC 6的药理学抑制减弱了肾小管细胞凋亡和阿基。HDAC6 反复低剂量顺铂治疗也高度诱导，这伴随着肾间质 纤维化、表皮生长因子受体（EGFR）和自噬的持续活化以及脱乙酰化 α-微管蛋白是纤毛解体的关键过程。此外，顺铂治疗诱导了原发性肝癌的缩短。 纤毛较短的细胞对顺铂诱导的顺铂敏感， 凋亡这些研究为HDAC 6可能介导顺铂诱导的肾损害提供了初步证据。 其机制可能涉及EGFR、自噬和纤毛解体。这些数据， 与已知的HDAC 6在肿瘤中的促癌作用一起，导致我们的假设， HDAC 6可以在顺铂化疗期间保护肾脏，同时增强其在肿瘤中的抗癌功效。 从机制上讲，HDAC 6可能通过激活EGFR而导致顺铂诱导的肾脏问题 自噬和初级纤毛的解体。为了验证这些假设，我们将 确定（1）HDAC 6的阻断是否可以在顺铂治疗期间保护肾脏，同时增强肾功能。 （2）HDAC 6是否有助于顺铂诱导的肾损伤、纤维化和 慢性肾脏病的持续激活EGFR和自噬;和（3）是否HDAC 6介导的纤毛解体 缓解顺铂治疗后的肾损伤、纤维化和CKD。这个多PI项目利用了 庄守刚博士在EGFR信号传导和表观遗传调控方面的互补专业知识， 郑东在自噬与顺铂肾毒性中的作用。成功完成拟议的研究将确定 HDAC 6抑制对顺铂诱导的肾损伤和纤维化的治疗作用，阐明HDAC 6抑制对顺铂诱导的肾损伤和纤维化的治疗作用。 潜在的机制，并确定一种新的策略，保护肾脏，同时提高化疗 功效