Endogenous Modulation of Cochlear Injury

描述(由申请人提供)：顺铂是当前化疗方案的重要组成部分。不幸的是，顺铂经常引起双侧且不可逆的耳毒性。这对听力损失严重阻碍语言、认知和社会发展的幼儿来说尤其具有挑战性。因此，迫切需要新药来降低顺铂的耳毒性。我们实验室最近的研究表明，单次经鼓室注射辣椒素(TRPV1激动剂)可导致一过性听力损失和炎性细胞因子的一过性增加。令人惊讶的是，经鼓室注射辣椒素可减轻顺铂的耳毒性。初步数据显示，口服辣椒素还可以减少顺铂诱导的听性脑干反应(ABER)阈值漂移。我们的体外研究表明，辣椒素的“预适应”效应是瞬时上调STAT1的结果。辣椒素激活STAT1可以修饰或隔离STAT1，从而阻止其在随后被顺铂攻击时与p53的相互作用。或者，辣椒素可以激活STAT1(即增加其磷酸化)，这与顺铂不同。辣椒素还可激活细胞保护性STAT蛋白(如STAT3)。辣椒素还可以增加耳蜗大麻素(CB)的表达，这可能是一种细胞保护作用。在UB/OC1细胞中的初步实验表明，辣椒素上调了这些细胞中的CB受体。在AIM 1中的实验将证实口服辣椒素对顺铂耳毒性的疗效，随后的3个AIMS将阐明其保护机制。目的2研究辣椒素对顺铂耳毒性保护作用的分子基础。假设辣椒素激活STAT1(通过介导Ser727和Tyr701的磷酸化)，从而隔离(或下调)它，从而减少可被顺铂激活的STAT1的可用性。目的3验证辣椒素通过激活或增加耳蜗CB受体的表达对顺铂耳毒性起到保护作用的假说。CB的激活在体外可降低顺铂的耳毒性，并在许多报道中显示出抗炎和神经保护作用。目的4将验证这样的假设，即基因阵列将显示辣椒素、顺铂和顺铂+辣椒素处理的大鼠耳蜗感兴趣基因的变化。目的5将确定辣椒素是否干扰或实际上增强顺铂的抗肿瘤效果。这项研究将为改善顺铂耳毒性提供新的保护性口腔治疗方法。

DESCRIPTION (provided by applicant): Cisplatin is a critical component of current chemotherapy regimens. Unfortunately, cisplatin frequently causes ototoxicity that is bilateral and irreversible. This is particularly challenging in young children in whom hearing loss severely hampers speech, cognitive and social development. Thus, there is an urgent need for new drugs to reduce cisplatin ototoxicity. Recent studies from our laboratory have shown that a single transtympanic injection of capsaicin (TRPV1 agonist) produced transient hearing loss and temporary increases in inflammatory cytokines. Surprisingly, pretreatment with transtympanic capsaicin alleviated cisplatin ototoxicity. Preliminary data show that oral capsaicin also reduces cisplatin-induced auditory brain stem response (ABER) threshold shifts. Our in vitro studies suggest that capsaicin's "preconditioning" effect results from transient STAT1 up-regulation. Activation of STAT1 by capsaicin may modify or sequester STAT1, preventing its interaction with p53 when cochlear cells are subsequently challenged by cisplatin. Alternatively, capsaicin could activate STAT1 (i.e. increase its phosphorylation) differently from cisplatin. Capsaicin could also activate cytoprotective STAT proteins (such as STAT3). Capsaicin can also increase cannabinoid (CB) expression in the cochlea, which can be cytoprotective. Preliminary experiments in UB/OC1 cells show that capsaicin up-regulates CB receptors in these cells. Experiments in aim1 should confirm the efficacy of oral capsaicin against cisplatin ototoxicity and the subsequent 3 aims will elucidate mechanisms of protection. Aim 2 will determine the molecular basis of capsaicin-mediated protection against cisplatin ototoxicity. The hypothesis is that capsaicin activates STAT1 (by mediating Ser727 and Tyr701 phosphorylation) which sequesters (or down-regulates) it, thereby decreasing the availability of STAT1 accessible for activation by cisplatin. Aim 3 will test the hypothesis that capsaicin-mediated protection against cisplatin ototoxicity by activation, or increasing the expression, of CB receptors in the cochlea. CB activation reduces cisplatin ototoxicity in vitro and has demonstrated anti-inflammatory and neuroprotective effects in numerous reports. Aim 4 will test the hypothesis that Gene Array will demonstrate changes in genes of interest in the cochlea of rats treated with capsaicin, cisplatin and cisplatin plus capsaicin. Aim 5 will determine whether capsaicin interferes with or actually enhances the antitumor efficacy of cisplatin. This research will offer great promise to provide novel protective oral treatments to ameliorate cisplatin ototoxicity.