Adult stem cells are present in a variety of tissues and organs including the cochlea, where they contribute to tissue homeostasis and plasticity by replacing or repairing injured cells throughout life. Nonsensory cells such as fibrocytes and intermediate cells in the lateral wall ofthe cochlea play an important role in the production of the endocochlear potential (EP). These cells have been shown to undergo continuous replenishment in the cochlea of young animals but this cell turnover decreases with age. Neural crest-derived stem cells (NCSCs), give rise to a wide variety of mesenchymal cell types including nonsensory cells in the cochlear lateral wall and changes in their activity may lead to the decrease in nonsensory cells with age which is a major pathological feature of metabolic presbyacusis. The maintenance and self-renewal of NCSCs is dependent on the integrity ofthe extracellular matrix (ECM). Our recent studies have shown a significant decline in the number of NCSC-like cells in the aged mouse cochlea as compared to younger controls. Parallel gene and protein analyses have revealed that the expression of genes for versican and several other ECM proteins in cochlear tissues is down-regulated with age in adult mice. We have also found that versican and its associated ECM proteins are present within the cochlear sphere niche and that depletion of versican results in elevated auditory thresholds in young adult mice. Analysis of microRNA (miRNA) levels in CBA/CaJ mice revealed an up-regulation of several ECM regulatory miRNAs at the age when lateral wall degeneration and EP declines first appear. Based on these findings, we hypothesize that age-dependent changes in ECM components and their regulatory molecules cause a reduction in the number and declines in the function of NCSCs, resulting in a depletion of non-sensory cells in the cochlear lateral wall and subsequent hearing loss.
Three specific aims are proposed.
Aim 4. 1 determines the role of NCSCs in pathological alterations ofthe cochlear lateral wall and in the loss of auditory function in older mouse and human ears.
Aim 4. 2 tests the hypothesis that age-related ECM changes are responsible for the reduced number and functional declines of NCSCs in the cochlear lateral wall.
Aim 4. 3 identifies the miRNAs that regulate age-related changes in ECM components in metabolic presbyacusis using mouse models and human cochlear tissues obtained from temporal bone donors. These experiments will enhance our understanding ofthe fundamental cellular and molecular mechanisms responsible for cochlear lateral wall dysfunction with age and the resultant metabolic presbyacusis.

Public Health Relevance

The proposed experiments will generate new knowledge about the contribution of adult stem cells and their associated microenvironmental factors to functional changes ofthe cochlear lateral wall in older humans and their relation to age-related hearing loss. This information will be of great importance to the development of new methods for diagnosis and treatment of hearing loss and other age-related degenerative diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute on Deafness and Other Communication Disorders (NIDCD)
Type
Specialized Center (P50)
Project #
5P50DC000422-29
Application #
9205508
Study Section
Special Emphasis Panel (ZDC1)
Project Start
Project End
Budget Start
2017-01-01
Budget End
2017-12-31
Support Year
29
Fiscal Year
2017
Total Cost
Indirect Cost
Name
Medical University of South Carolina
Department
Type
DUNS #
183710748
City
Charleston
State
SC
Country
United States
Zip Code
29403
Lewis, Morag A; Nolan, Lisa S; Cadge, Barbara A et al. (2018) Whole exome sequencing in adult-onset hearing loss reveals a high load of predicted pathogenic variants in known deafness-associated genes and identifies new candidate genes. BMC Med Genomics 11:77
Bologna, William J; Vaden Jr, Kenneth I; Ahlstrom, Jayne B et al. (2018) Age effects on perceptual organization of speech: Contributions of glimpsing, phonemic restoration, and speech segregation. J Acoust Soc Am 144:267
Panganiban, Clarisse H; Barth, Jeremy L; Darbelli, Lama et al. (2018) Noise-induced dysregulation of Quaking RNA binding proteins contributes to auditory nerve demyelination and hearing loss. J Neurosci :
Chiarello, Christine; Vaden Jr, Kenneth I; Eckert, Mark A (2018) Orthographic influence on spoken word identification: Behavioral and fMRI evidence. Neuropsychologia 111:103-111
Harris, Kelly C; Vaden Jr, Kenneth I; McClaskey, Carolyn M et al. (2018) Complementary metrics of human auditory nerve function derived from compound action potentials. J Neurophysiol 119:1019-1028
McRackan, Theodore R; Fabie, Joshua E; Burton, Jane A et al. (2018) Earphone and Aided Word Recognition Differences in Cochlear Implant Candidates. Otol Neurotol 39:e543-e549
Dubno, Judy R (2018) Beyond the audiogram: application of models of auditory fitness for duty to assess communication in the real world. Int J Audiol 57:321-322
McRackan, Theodore R; Clinkscales, William B; Ahlstrom, Jayne B et al. (2018) Factors associated with benefit of active middle ear implants compared to conventional hearing aids. Laryngoscope 128:2133-2138
Dias, James W; McClaskey, Carolyn M; Harris, Kelly C (2018) Time-Compressed Speech Identification Is Predicted by Auditory Neural Processing, Perceptuomotor Speed, and Executive Functioning in Younger and Older Listeners. J Assoc Res Otolaryngol :
Worley, Mitchell L; Schlosser, Rodney J; Soler, Zachary M et al. (2018) Age-related differences in olfactory cleft volume in adults: A computational volumetric study. Laryngoscope :

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