Heat Shock Protein-Induced Protection Against Cisplatin-Induced Hair Cell Death

热激蛋白诱导的针对顺铂诱导的毛细胞死亡的保护

• 批准号: 7804981
• 负责人: Tiffany Gray Baker
• 金额: $ 3.45万
• 依托单位: MEDICAL UNIVERSITY OF SOUTH CAROLINA
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-28 至 2015-09-27
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7804981
• 关键词: Adult; Adverse effects; Aminoglycosides; Apoptosis; Apoptotic; Biological Models; Cell Death; Cell Survival; Cells; Cessation of life; Chemicals; Cisplatin; Cochlea; DNA Adducts; DNA Damage; Data; Dose; Dose-Limiting; Event; Genotoxic Stress; Goals; Hair Cells; Heat shock proteins; Heat-Shock Response; In Vitro; Kidney; Knockout Mice; Labyrinth; Malignant Neoplasms; Mediating; Mediator of activation protein; Mus; Neonatal; Patients; Pharmaceutical Preparations; Play; Prevention; Production; Protein p53; Proteins; Proximal Kidney Tubules; Quality of life; Rattus; Reactive Oxygen Species; Relative (related person); Resistance; Role; STAT protein; STAT1 protein; Sensory Hair; Signal Transduction; Signaling Molecule; Stress; System; TP53 gene; Transgenic Mice; Up-Regulation; Utricle structure; Western Blotting; cancer cell; design; hearing impairment; improved; in vivo; nephrotoxicity; ototoxicity; overexpression; preconditioning; prevent; pro-apoptotic protein; protective effect; public health relevance; research study; response

DESCRIPTION (provided by applicant): Cisplatin has been successfully used to treat of a variety of cancers since the 1970s. However, patients who receive cisplatin can suffer from dose-limiting side-effects which include nephrotoxicity and ototoxicity. The ototoxic effects of cisplatin involve in part the death of sensory hair cells of the inner ear. Cisplatin causes cell death by forming DNA adducts and increasing the pool of reactive oxygen species (ROS) in cells. Two pro-apoptotic proteins known to play roles in cisplatin-induced cell death are p53 and the signal transducer and activator of transcription protein-1 (STAT-1). p53 is a major mediator of cisplatin-induced death of cancer cells (reviewed by Siddik 2003). However, recent evidence indicates that p53 is not required for cisplatin-induced death of renal proximal tubule cells in the kidney (Jiang et al. 2009). The role of p53 in cisplatin-induced death of hair cells has not been determined. Cisplatin-induced hair cell death is dependent on STAT-1 activation (Schmitt et al. 2009). Heat shock preconditioning, which results in upregulation of heat shock proteins (Hsps), inhibits cisplatin-induced hair cell death (Cunningham and Brandon 2006). One of these Hsps, Hsp32, has been shown to inhibit cisplatin-induced hair cell death in neonatal rat cochlea in vitro (Kim et al. 2006). Hsp70 is the most stress-inducible Hsp, and it can protect hair cells from aminoglycoside induced death both in vitro and in vivo (Taleb et al. 2008; Taleb et al. 2009). Both Hsp70 and Hsp32 have been shown to modulate the activation of either p53 or STAT-1. The experiments in this proposal are designed to examine the role of p53 in mediating cisplatin-induced hair cell death and to elucidate the mechanism(s) underlying the protective effects of Hsp32 and Hsp70. PUBLIC HEALTH RELEVANCE: The prevention of hearing loss as a result of cisplatin treatment is necessary in order to maintain the best possible quality of life for patients receiving this drug. This project is designed to improve our understanding of cisplatin-induced hearing loss and to advance the goal of developing a co-therapy aimed at preventing cisplatin-induced hearing loss.

描述（由申请人提供）：自 20 世纪 70 年代以来，顺铂已成功用于治疗多种癌症。然而，接受顺铂的患者可能会出现剂量限制性副作用，包括肾毒性和耳毒性。顺铂的耳毒性作用部分涉及内耳感觉毛细胞的死亡。顺铂通过形成 DNA 加合物并增加细胞内活性氧 (ROS) 库而导致细胞死亡。已知在顺铂诱导的细胞死亡中发挥作用的两种促凋亡蛋白是 p53 和转录蛋白 1 (STAT-1) 的信号转导子和激活子。 p53 是顺铂诱导的癌细胞死亡的主要介质（Siddik 2003 年综述）。然而，最近的证据表明，顺铂诱导的肾近曲小管细胞死亡不需要 p53（Jiang 等，2009）。 p53 在顺铂诱导的毛细胞死亡中的作用尚未确定。顺铂诱导的毛细胞死亡依赖于 STAT-1 激活（Schmitt et al. 2009）。热休克预处理会导致热休克蛋白 (Hsps) 上调，抑制顺铂诱导的毛细胞死亡 (Cunningham 和 Brandon 2006)。其中一种 Hsp，Hsp32，已被证明可以在体外抑制新生大鼠耳蜗中顺铂诱导的毛细胞死亡（Kim 等人，2006）。 Hsp70 是应激诱导性最强的 Hsp，它可以在体外和体内保护毛细胞免受氨基糖苷类诱导的死亡（Taleb 等人，2008 年；Taleb 等人，2009 年）。 Hsp70 和 Hsp32 均已被证明可以调节 p53 或 STAT-1 的激活。本提案中的实验旨在检查 p53 在介导顺铂诱导的毛细胞死亡中的作用，并阐明 Hsp32 和 Hsp70 保护作用的机制。 公共卫生相关性：为了使接受该药物的患者保持最佳的生活质量，有必要预防顺铂治疗导致的听力损失。该项目旨在提高我们对顺铂引起的听力损失的了解，并推进开发旨在预防顺铂引起的听力损失的联合疗法的目标。