The goal of this award is to establish a successful research program and develop my career as a physician-scientist. As a pediatric otolaryngologist with a clinical focus on hearing loss, I am confronted daily with young children with the diagnosis of hearing loss. Progressive hearing loss is a frustrating problem for children, parents, and physicians. I hope to establish a research program that will identify new protective compounds that can prevent hearing loss, as well as identify potentially ototoxic drugs amongst those that are already in use today. As a physician, I have had a somewhat fragmented exposure to basic science research. The training period associated with this award would allow me to broaden my knowledge of auditory neuroscience, particularly in the realms of molecular biology, protein purification, and zebrafish biology. Knowledge in these areas will be critical for my development as a physician-scientist and for the development of this research program. This proposal describes a series of experiments that will identify and characterize compounds that are protective or toxic to hair cells of the inner ear. Candidate protective/toxic drugs will be identified with a high throughput screen using the zebrafish lateral line. The effects of these drugs will then be confirmed in vitro with mouse utricles, and in vivo on adult mice. Candidate protective and toxic drugs will be tested against each other to further define their protective and toxic qualities. Finally, protective and toxic drugs will be evaluated on a molecular level by determining their effects on markers of cell death. Compounds with unknown targets will be investigated through protein purification.
This research is very relevant to public health. Hearing loss is a disorder which affects millions of people globally. It can severely impair a person's ability to communicate. This project seeks to identify drugs that can prevent the progression of hearing loss, and identify drugs that have the potential to cause hearing loss.
|Thomas, Andrew J; Wu, Patricia; Raible, David W et al. (2015) Identification of small molecule inhibitors of cisplatin-induced hair cell death: results of a 10,000 compound screen in the zebrafish lateral line. Otol Neurotol 36:519-25|
|Thomas, Andrew J; Hailey, Dale W; Stawicki, Tamara M et al. (2013) Functional mechanotransduction is required for cisplatin-induced hair cell death in the zebrafish lateral line. J Neurosci 33:4405-14|
|Esterberg, Robert; Coffin, Allison B; Ou, Henry et al. (2013) Fish in a Dish: Drug Discovery for Hearing Habilitation. Drug Discov Today Dis Models 10:|
|Ou, Henry C; Lin, Vincent; Rubel, Edwin W (2013) ""In-bone"" utricle cultures--a simplified, atraumatic technique for in situ cultures of the adult mouse (Mus musculus) utricle. Otol Neurotol 34:353-9|
|Ou, Henry; Simon, Julian A; Rubel, Edwin W et al. (2012) Screening for chemicals that affect hair cell death and survival in the zebrafish lateral line. Hear Res 288:58-66|
|Ou, Henry C; Keating, Sarah; Wu, Patricia et al. (2012) Quinoline ring derivatives protect against aminoglycoside-induced hair cell death in the zebrafish lateral line. J Assoc Res Otolaryngol 13:759-70|
|Hirose, Yoshinobu; Simon, Julian A; Ou, Henry C (2011) Hair cell toxicity in anti-cancer drugs: evaluating an anti-cancer drug library for independent and synergistic toxic effects on hair cells using the zebrafish lateral line. J Assoc Res Otolaryngol 12:719-28|
|Ou, Henry C; Santos, Felipe; Raible, David W et al. (2010) Drug screening for hearing loss: using the zebrafish lateral line to screen for drugs that prevent and cause hearing loss. Drug Discov Today 15:265-71|