Hearing is impaired in more than 10% of the human population. Despite significant progress in neonatal regeneration of mammalian cochlear hair cells (HCs), such regeneration in adults has proved extremely difficult. While gamma secretase inhibitors have shown some promise in regenerating noise-damaged auditory HCs in adult mice, no drugs have been proven effective for auditory HC regeneration in adult humans. Interestingly, we recently demonstrated that supporting cells (which surround hair cells) can be converted to HCs in mature cochleae through combined manipulation of two key genes, one of which (p27Kip1 or p27) is inactivated and one of which (Atoh1) is activated. These findings led us to screen for small-molecule inhibitors of p27 and to characterize them in cell lines. We propose to test the inhibitory effects of these lead compounds in cochlear explants and in vivo in adult wild-type and transgenic mice, with or without noise damage. These exploratory studies will provide the key """"""""proof of concept"""""""" for using small-molecule inhibitors of p27, together with small-molecule activators of Atoh1, to regenerate damaged auditory HCs in adult mammals. The final lead compounds identified here will advance to the drug development pipeline for optimization, selection, and preclinical safety analysis, and eventually to clinical trials for HC regeneration in humans. These studies may lead to a breakthrough in the treatment of hearing loss caused by noise, antibiotics, chemotherapy, or age.

Public Health Relevance

Hearing impairment affects more than 10% human population. To treat hearing loss, we propose to develop drugs against a key gene that can be used to regenerate sensory cells in the inner ear. These studies may lead to a breakthrough in the treatment of hearing loss caused by noise, antibiotics, chemotherapy, or age.

Agency
National Institute of Health (NIH)
Institute
National Institute on Deafness and Other Communication Disorders (NIDCD)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21DC013879-01
Application #
8682710
Study Section
Auditory System Study Section (AUD)
Program Officer
Freeman, Nancy
Project Start
2014-08-01
Project End
2016-07-31
Budget Start
2014-08-01
Budget End
2015-07-31
Support Year
1
Fiscal Year
2014
Total Cost
Indirect Cost
Name
St. Jude Children's Research Hospital
Department
Type
DUNS #
City
Memphis
State
TN
Country
United States
Zip Code
38105
Liu, Xiaoyu; Yamashita, Tetsuji; Chen, Qun et al. (2015) Interleukin 1 type 1 receptor restore: a genetic mouse model for studying interleukin 1 receptor-mediated effects in specific cell types. J Neurosci 35:2860-70
Iconaru, Luigi I; Ban, David; Bharatham, Kavitha et al. (2015) Discovery of Small Molecules that Inhibit the Disordered Protein, p27(Kip1). Sci Rep 5:15686
Kuo, Bryan R; Baldwin, Emily M; Layman, Wanda S et al. (2015) In Vivo Cochlear Hair Cell Generation and Survival by Coactivation of β-Catenin and Atoh1. J Neurosci 35:10786-98
Walters, Bradley J; Zuo, Jian (2015) A Sox10(rtTA/+) Mouse Line Allows for Inducible Gene Expression in the Auditory and Balance Organs of the Inner Ear. J Assoc Res Otolaryngol 16:331-45
Wang, Tian; Chai, Renjie; Kim, Grace S et al. (2015) Lgr5+ cells regenerate hair cells via proliferation and direct transdifferentiation in damaged neonatal mouse utricle. Nat Commun 6:6613
Walters, Brandon J; Diao, Shiyong; Zheng, Fei et al. (2015) Pseudo-immortalization of postnatal cochlear progenitor cells yields a scalable cell line capable of transcriptionally regulating mature hair cell genes. Sci Rep 5:17792
Xu, Heng; Robinson, Giles W; Huang, Jie et al. (2015) Common variants in ACYP2 influence susceptibility to cisplatin-induced hearing loss. Nat Genet 47:263-6
Mellado Lagarde, Marcia M; Wan, Guoqiang; Zhang, LingLi et al. (2014) Spontaneous regeneration of cochlear supporting cells after neonatal ablation ensures hearing in the adult mouse. Proc Natl Acad Sci U S A 111:16919-24
Walters, Bradley J; Liu, Zhiyong; Crabtree, Mark et al. (2014) Auditory hair cell-specific deletion of p27Kip1 in postnatal mice promotes cell-autonomous generation of new hair cells and normal hearing. J Neurosci 34:15751-63
Cox, Brandon C; Dearman, Jennifer A; Brancheck, Joseph et al. (2014) Generation of Atoh1-rtTA transgenic mice: a tool for inducible gene expression in hair cells of the inner ear. Sci Rep 4:6885

Showing the most recent 10 out of 13 publications