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.

Agency
National Institute of Health (NIH)
Institute
National Institute on Deafness and Other Communication Disorders (NIDCD)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21DC010909-02
Application #
8286223
Study Section
Auditory System Study Section (AUD)
Program Officer
Freeman, Nancy
Project Start
2011-07-01
Project End
2014-06-30
Budget Start
2012-07-01
Budget End
2014-06-30
Support Year
2
Fiscal Year
2012
Total Cost
$190,000
Indirect Cost
$65,000
Name
Washington University
Department
Otolaryngology
Type
Schools of Medicine
DUNS #
068552207
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
Slattery, Eric L; Oshima, Kazuo; Heller, Stefan et al. (2014) Cisplatin exposure damages resident stem cells of the mammalian inner ear. Dev Dyn 243:1328-37
Audo, Isabelle; Warchol, Mark E (2012) Retinal and cochlear toxicity of drugs: new insights into mechanisms and detection. Curr Opin Neurol 25:76-85