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

描述(申请人提供)：自20世纪70年代以来，顺铂已成功用于治疗各种癌症。然而，接受顺铂治疗的患者可能会出现剂量限制的副作用，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加合物和增加细胞内的活性氧(ROS)池而导致细胞死亡。已知的在顺铂诱导的细胞死亡中起作用的两个促凋亡蛋白是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，顺铂诱导的肾脏近端小管细胞死亡不需要p53(酱等人。2009年)。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的激活(Schmitt等人。2009年)。热休克预适应可导致热休克蛋白(HSPs)表达上调，从而抑制顺铂诱导的毛细胞死亡(Cunningham和Brandon 2006)。其中一种热休克蛋白，HSP32，已被证明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)。HSP70是应激诱导最强的热休克蛋白，在体外和体内都能保护毛细胞免受氨基糖苷类药物诱导的死亡(Taleb等人)。2008年；Taleb等人。2009年)。Hsp70和Hsp32都被证明可以调节P53或STAT-1的激活。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HSP32和HSP70保护作用的机制(S)。 公共卫生相关性：为了保持接受该药物的患者尽可能好的生活质量，预防顺铂治疗导致的听力损失是必要的。该项目旨在提高我们对顺铂所致听力损失的认识，并推进旨在预防顺铂所致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.