Auditory neuropathy caused by the loss of spiral ganglion neurons (SGN) loss results in hearing loss. Standard remediation, such as the use of hearing aids and cochlear implants are ineffective after the loss of SGNs. Many daily ototoxic insults such as loud sounds result in acute loss of synaptic contacts, degeneration of the auditory nerve fibers and loss of SGN over an extended period of time. Given an ever-increasing aging population that is exposed to loud sounds from portable music players, degeneration of SGNs will become a major health concern. Stem cell replacement therapies hold great promise to repopulate lost SGNs and restore hearing function. In order to properly use stem cells to treat hearing loss, identifying genes that can recapitulate SGN development in stem cells will accelerate efforts for replacement therapies. Using an immortalized otic progenitor (iMOP) cell line, we identified novel candidate transcription factors and chromatin remodeling proteins that are important in SGN development and regeneration. One of the candidates is Chd4, a chromatin remodeling protein that is part of the nucleosome remodeling and deacetylase (NuRD) complex. We propose that Chd4 is essential for neuronal specification, axon guidance and synaptogenesis during SGN development. We will test the role of Chd4 in specifying neuronal fate and neurite extension using iMOP-derived neurons and an inner ear Chd4 knockout animal. Using an iMOP-derived neuron and deafferented cochlear explant co-culture system, we will study how Chd4 promotes axon guidance to the hair cell targets. Finally, we will generate a tamoxifen inducible Chd4 knockout animal to determine defects in synaptogenesis during SGN maturation.

Public Health Relevance

Auditory neuropathy caused by the loss of spiral ganglion neurons (SGN) currently has no treatment options. Stem cell replacement therapy has emerged as a promising avenue to address this significant health concern. Identifying and understanding the function of genes involved in SGN development will accelerate efforts for stem cell therapies.

Agency
National Institute of Health (NIH)
Institute
National Institute on Deafness and Other Communication Disorders (NIDCD)
Type
Research Project (R01)
Project #
5R01DC015000-04
Application #
9692255
Study Section
Auditory System Study Section (AUD)
Program Officer
Freeman, Nancy
Project Start
2016-05-15
Project End
2021-04-30
Budget Start
2019-05-01
Budget End
2020-04-30
Support Year
4
Fiscal Year
2019
Total Cost
Indirect Cost
Name
Rutgers University
Department
Anatomy/Cell Biology
Type
Schools of Arts and Sciences
DUNS #
001912864
City
Piscataway
State
NJ
Country
United States
Zip Code
08854
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