EFFECTS OF CISPLATIN ON INNER EAR STEM CELLS

描述（由申请人提供）：顺铂是一种广泛使用的化疗药物，对卵巢、睾丸、膀胱和头颈部肿瘤都有很高的疗效。顺铂治疗的一个后果是耳毒性，约30%的接受治疗的患者会出现耳毒性，并可能导致永久性听力丧失。不幸的是，通常没有合适的顺铂治疗方案，因此顺铂性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对毛细胞的损伤上。然而，最近我们发现顺铂治疗对禽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，在体外顺铂耳毒性作用后，禽类内耳完全不能再生。对这些现象的进一步了解将揭示顺铂对内耳的作用和非哺乳动物耳朵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鸟类支持细胞核DNA中“铂加合物”的形成，以及这种DNA损伤是否与缺乏再生能力有关。接下来，我们将进一步表征顺铂对鸟类耳蜗的影响，并确定体内顺铂耳毒性是否会损害耳蜗的再生。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)引起耳蜗支持细胞的结构改变。由于健康的支持细胞对于未来听力损失的再生疗法至关重要，因此我们有必要了解这些细胞如何受到耳毒性药物的影响

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.