EFFECTS OF CISPLATIN ON INNER EAR STEM CELLS

描述(申请人提供)：顺铂是一种广泛使用的化疗药物，对卵巢、睾丸、膀胱和头颈部肿瘤非常有效。顺铂治疗的一个后果是耳毒性，大约30%的接受治疗的人会发生耳毒性，并可能导致永久性听力损失。不幸的是，顺铂治疗往往没有合适的替代品，因此顺铂所致的听力损失是一个严重的临床问题。目前对顺铂耳毒性的细胞机制知之甚少，以往的研究大多集中在毛细胞损伤方面。然而，最近我们发现顺铂治疗对鸟耳的支持细胞也有直接和持久的影响。此外，我们的研究表明，在体外，鸟类内耳完全不能在顺铂耳毒性后再生。对这些现象的进一步了解应该会揭示顺铂对内耳的作用以及非哺乳动物耳朵的感觉再生机制的新见解。在拟议的研究中，我们将首先确定顺铂是否会导致禽类支持细胞核DNA中形成“铂加合物”，以及这种DNA损伤是否与缺乏再生能力有关。接下来，我们将进一步研究顺铂对鸟类耳蜗的影响，并确定体内顺铂耳毒性后再生是否受损。第三组研究将集中在哺乳动物的耳朵上。我们将确定顺铂是否：(1)损害小鼠Corti器官内的核DNA，(2)导致耳蜗支持细胞的结构变化。由于健康的支持细胞将对未来的听力损失再生治疗至关重要，因此我们必须了解这些细胞是如何受到耳毒性药物的影响的。 公共卫生相关性：顺铂是一种高效的化疗药物，也可能导致永久性听力损失。拟议的研究将表征顺铂对内耳毛细胞和支持细胞的影响。更全面地了解顺铂对支持细胞的影响，对于诱导人耳顺铂耳毒性后的感觉再生具有重要意义。

DESCRIPTION (provided by applicant): Cisplatin is a widely-used chemotherapeutic agent that is highly effective against ovarian, testicular, bladder, and head and neck tumors. One consequence of cisplatin treatment is ototoxicity, which occurs in about 30% of treated individuals and can result in permanent hearing loss. Unfortunately, there are often no suitable alternatives for cisplatin treatment, so cisplatin-induced hearing loss is a serious clinical problem. Little is known about the cellular mechanisms of cisplatin ototoxicity, and most prior studies have focused on injury to hair cells. Recently, however, we have found that cisplatin treatment also has direct and long-lasting effects on supporting cells of the avian ear. Moreover, our studies show that the avian inner ear is completely unable to regenerate after cisplatin ototoxicity in vitro. An enhanced understanding of these phenomena should reveal new insights into both the actions of cisplatin on the inner ear and the mechanisms of sensory regeneration in the nonmammalian ear. In the proposed studies, we will first determine whether cisplatin causes the formation of 'platinum adducts' in nuclear DNA of avian supporting cells and whether such DNA damage is correlated with the lack of regenerative ability. Next, we will further characterize the effects of cisplatin on the avian cochlea and determine whether regeneration is impaired after cisplatin ototoxicity in vivo. A third set of studies will focus on the mammalian ear. We will determine whether cisplatin: (1) damages nuclear DNA within the mouse organ of Corti and (2) causes structural changes in cochlear supporting cells. Since healthy supporting cells will be essential for future regenerative therapies for hearing loss, it is essential that we understand how those cells are affected by exposure to ototoxic drugs PUBLIC HEALTH RELEVANCE: Cisplatin is a highly effective chemotherapeutic agent that can also cause permanent hearing loss. The proposed studies will characterize the effects of cisplatin on inner ear hair cells and supporting cells. A more-complete understanding of the impact of cisplatin on supporting cells will be valuable towards efforts for inducing sensory regeneration in the human ear after cisplatin ototoxicity.