The Usher Syndrome (USH) is a clinically and genetically heterogeneous disorder characterized by congenital deafness and retinitis pigmentosa. It is the most common cause of deafness accompanied by blindness. Hair cell replacement or regeneration therapies have not really solved the deafness problem of ear diseases. An alternative to replacing lost hair cells is to prevent their loss in the first place, which is a particularly promising line of investigation. Many USH patients will benefit from cochlear implants, but preservation of spiral ganglion cells is important for success of cochlear implants because a minimal density of spiral ganglion cells is required for effective cochlear implants. Residual hair cells present in the cochlea could promote the survival of spiral ganglion neurons by release of neurotrophic substances. Therefore, discovery of therapeutic targets that prevent hair cell death is the key to helping Usher 1 patients to respond to cochlear implants and other treatment options successfully. Mouse models facilitate experiments to determine the function of the various genes involved in Usher disease. We have developed mouse models for Usher syndrome. Thus, we propose the following specific aims: 1) identify the mutation in and characterize a new mouse deafness model (for Usher 1 syndrome and presbycusis) that provides an ideal window of time for evaluating drug therapy;2) identify key molecules and mechanisms that lead to hair cell death and hearing loss in the models for the Usher 1 syndrome;3) prove the concept that genetic hearing loss and hair cell death can be prevented by otoprotection therapy. Results of the proposed research will benefit human health.

Public Health Relevance

Usher Syndrome (USH) accounts for 6% of the congenitally deaf population and more than 50% of the deaf- blind population. Discovery of therapeutic targets that prevent hair cell death is the key to helping Usher 1 patients to respond to cochlear implants and other treatment options successfully. We propose to develop a new mouse deafness model, a model for Usher 1 syndrome and presbycusis, which has an ideal window of time for evaluating drug therapy.

National Institute of Health (NIH)
National Institute on Deafness and Other Communication Disorders (NIDCD)
Research Project (R01)
Project #
Application #
Study Section
Auditory System Study Section (AUD)
Program Officer
Watson, Bracie
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Case Western Reserve University
Schools of Medicine
United States
Zip Code
Henneman, Nathaniel F; Foster, Stephanie L; Chrenek, Micah A et al. (2018) Xanthohumol Protects Morphology and Function in a Mouse Model of Retinal Degeneration. Invest Ophthalmol Vis Sci 59:45-53
Li, Bo; Zheng, Tihua; Yan, Caifang et al. (2018) Chemical chaperone 4-phenylbutyrate prevents hearing loss and cochlear hair cell death in Cdh23erl/erl mutant mice. Neuroreport :
Wick, Cameron C; Lin, Sharon J; Yu, Heping et al. (2017) Treatment of ear and bone disease in the Phex mouse mutant with dietary supplementation. Am J Otolaryngol 38:44-51
Chrenek, Micah A; Nickerson, John M; Boatright, Jeffrey H (2016) Clustered Regularly Interspaced Short Palindromic Repeats: Challenges in Treating Retinal Disease. Asia Pac J Ophthalmol (Phila) 5:304-8
Schmidt, Robin H; Nickerson, John M; Boatright, Jeffrey H (2016) Exercise as Gene Therapy: BDNF and DNA Damage Repair. Asia Pac J Ophthalmol (Phila) 5:309-11
Bhatia, Shagun K; Rashid, Alia; Chrenek, Micah A et al. (2016) Analysis of RPE morphometry in human eyes. Mol Vis 22:898-916
Hu, J; Xu, M; Yuan, J et al. (2016) Tauroursodeoxycholic acid prevents hearing loss and hair cell death in Cdh23(erl/erl) mice. Neuroscience 316:311-20
Markand, Shanu; Baskin, Natecia L; Chakraborty, Ranjay et al. (2016) IRBP deficiency permits precocious ocular development and myopia. Mol Vis 22:1291-1308
Song, Yongdong; Fan, Zhaomin; Bai, Xiaohui et al. (2016) PARP-1-modulated AIF translocation is involved in streptomycin-induced cochlear hair cell death. Acta Otolaryngol 136:545-50
Gao, Su; Yu, Yang; Ma, Zhi-Yuan et al. (2015) NMDAR-Mediated Hippocampal Neuronal Death is Exacerbated by Activities of ASIC1a. Neurotox Res 28:122-37

Showing the most recent 10 out of 42 publications