Sensorineural hearing loss is caused by the death of hair cells in the organ of Corti, and once lost, cochlear hair cells in humans and other mammals do not regenerate. In contrast, non-mammalian vertebrates can functionally recover from deafening injury by mobilizing supporting cells to divide and differentiate to replace lost hair cells. Over the last 10 years, the consensus from many studies is that supporting cells in the embryonic and neonatal organ of Corti retain a limited capacity to divide and differentiate into hair cells under certain conditions, but that this ability declines precipitously prior to the onse of hearing. One facet of such an age-dependent decline in regenerative potential is the function of the transcription factor Atoh1. Ectopic expression of Atoh1 in embryonic or neonatal cochlear tissue can transform supporting cells or adjacent non-sensory into hair cells - but this ability appears to be severely diminished after the onset of hearing in mice. The goal of this proposal is to understand why the ability of Atoh1 to drive cochlear hair cell regeneration declines with age. Although there are many possible mechanisms for this age-dependent decline, we will test just two in the current proposal. First, we hypothesize that at least some of the transcriptional target of Atoh1 become epigenetically modified in supporting cells with age, rendering them unavailable for transcription. Our second hypothesis, which is not mutually exclusive with the first, is that Atoh1 requires transcriptional co-factors that are not present in the mature cochlea Studies from Drosophila and our preliminary data have identified the zinc finger transcription factor Gfi1 as a good candidate to potentiate the activity of Atoh1 during hair cell formation.

Public Health Relevance

The most common form of hearing loss is caused by the death of hair cells in the cochlea. Many animals such as birds, frogs and fish, are capable of regenerating their hair cells, and recent work has shown that young mammals are capable of a limited amount of regeneration. However, this ability disappears in mammals by the time they are old enough to hear, and in our proposal, we will test two different hypotheses as to why mature mammals are unable to regenerate their sensory hair cells.

Agency
National Institute of Health (NIH)
Institute
National Institute on Deafness and Other Communication Disorders (NIDCD)
Type
Research Project (R01)
Project #
5R01DC014832-03
Application #
9386746
Study Section
Auditory System Study Section (AUD)
Program Officer
Freeman, Nancy
Project Start
2015-12-01
Project End
2020-11-30
Budget Start
2017-12-01
Budget End
2018-11-30
Support Year
3
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Baylor College of Medicine
Department
Neurosciences
Type
Schools of Medicine
DUNS #
051113330
City
Houston
State
TX
Country
United States
Zip Code
77030
Choo, Daniel I; Tawfik, Kareem O; Martin, Donna M et al. (2017) Inner ear manifestations in CHARGE: Abnormalities, treatments, animal models, and progress toward treatments in auditory and vestibular structures. Am J Med Genet C Semin Med Genet 175:439-449
Semerci, Fatih; Choi, William Tin-Shing; Bajic, Aleksandar et al. (2017) Lunatic fringe-mediated Notch signaling regulates adult hippocampal neural stem cell maintenance. Elife 6:
Xie, Wei Rose; Jen, Hsin-I; Seymour, Michelle L et al. (2017) An Atoh1-S193A Phospho-Mutant Allele Causes Hearing Deficits and Motor Impairment. J Neurosci 37:8583-8594
Lee, Min Young; Hackelberg, Sandra; Green, Kari L et al. (2017) Survival of human embryonic stem cells implanted in the guinea pig auditory epithelium. Sci Rep 7:46058
Wang, Guo-Peng; Basu, Ishani; Beyer, Lisa A et al. (2017) Severe streptomycin ototoxicity in the mouse utricle leads to a flat epithelium but the peripheral neural degeneration is delayed. Hear Res 355:33-41
Maass, Juan C; Gu, Rende; Cai, Tiantian et al. (2016) Transcriptomic Analysis of Mouse Cochlear Supporting Cell Maturation Reveals Large-Scale Changes in Notch Responsiveness Prior to the Onset of Hearing. PLoS One 11:e0167286
Kurioka, Takaomi; Lee, Min Young; Heeringa, Amarins N et al. (2016) Selective hair cell ablation and noise exposure lead to different patterns of changes in the cochlea and the cochlear nucleus. Neuroscience 332:242-57
Smith, Michael E; Groves, Andrew K; Coffin, Allison B (2016) Editorial: Sensory Hair Cell Death and Regeneration. Front Cell Neurosci 10:208