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

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遭受剂量限制性副作用，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加合物和增加细胞中的活性氧（ROS）库而引起细胞死亡。已知在顺铂诱导的细胞死亡中起作用的两种促凋亡蛋白是p53和信号转导和转录激活蛋白-1（STAT-1）。p53是顺铂诱导的癌细胞死亡的主要介质（由Siddik 2003综述）。然而，最近的证据表明，顺铂诱导的肾脏近端小管细胞死亡不需要p53（Jiang et al. 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（施密特et al. 2009）。导致热休克蛋白（Hsps）上调的热休克预处理抑制顺铂诱导的毛细胞死亡（Cunningham和布兰登2006）。这些Hsps之一，Hsp 32，已显示在体外抑制顺铂诱导的新生大鼠耳蜗毛细胞死亡（Kim等人，2006）。Hsp 70是最具应激诱导性的Hsp，在体外和体内均可保护毛细胞免受氨基糖苷类诱导的死亡（Taleb et al. 2008; Taleb et al. 2009）。Hsp 70和Hsp 32均显示调节p53或STAT-1的活化。本实验旨在研究p53在顺铂诱导的毛细胞死亡中的作用，并阐明Hsp 32和Hsp 70保护作用的机制。 公共卫生相关性：预防顺铂治疗导致的听力损失是必要的，以保持接受这种药物的患者的最佳生活质量。该项目旨在提高我们对顺铂引起的听力损失的理解，并推进开发旨在预防顺铂引起的听力损失的联合治疗的目标。

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.