EFFECTS OF CISPLATIN ON INNER EAR STEM CELLS

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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