More than 28 million Americans and 360 million people worldwide have hearing loss according to World Health Organization. Most hearing loss is caused by damaged cochlear hair cells (HC), which do not regenerate in humans or other mammals. Usher Syndrome, Type ID (USH1D) or autosomal recessive deafness 12 (DFNB12) or some age-related hearing loss (AHL) involve mutations of the cadherin 23 (Cdh23) gene in humans and mouse models. We have reported a novel recessive mutation erlong (erl, symbol for the mutation; CDH23erl is the symbol for the mutated protein) characterized by progressive hearing loss beginning from postnatal day 27 (P27). Genetic mapping and sequencing analysis revealed a T208C transition causing an amino-acid substitution (S70P, renamed as S47P after adjusting for the signal sequence [Nature 2012, PMC3518760]). Hearing loss was associated with HC loss due to induction of apoptosis. Hearing was preserved (up to 35-dB improvement) in anti-apoptosis-treated erl/erl mutants with significant outer hair cell (OHC) protection. The short interval from normal hearing to deafness (P27-P90), and quick onset of hearing loss at high frequencies, makes this model ideal for evaluating otoprotective drugs. It is reported that some early-onset hearing loss patients had CDH23 mutations with the similar phenotypes as the erl/erl mutants (4). It is highly significant to further study this model. Thus we will test th hypothesis that the erl mutation causes CDH23erl protein retention in the endoplasmic reticulum (ER); thus inducing the Unfolded Protein Response (UPR). The UPR comprises a set of cellular signaling pathways present in mammalian cells that detects unfolded proteins in the ER and directs either protective or apoptotic actions taken by the cell. The UPR signaling acts cytoprotectively by elevating chaperone gene expressions and decreasing unfolded protein levels. The UPR signaling is also well established to induce apoptosis when its cytoprotective functions decline. We will investigate the role of the UPR signaling in the pathogenesis of DFNB12/AHL using the genetic animal models of the Cdh23 gene. Specifically, this project aims to: (1) Test the hypothesis that the CDH23erl protein is accumulated in the ER area. (2) Test the hypothesize that the ER accumulation of CDH23erl protein in the ER causes UPR and ER stress (ERS) that leads to apoptosis through the eukaryotic initiation factor 2 alpha (eIF2?) - CHOP (CCAAT/-enhancer-binding protein homologous protein) pathway. (3) Test the hypothesis that the delayed onset of HL is due to over-adaptation, increased protein synthesis rates in HCs and increased sensitivity of HCs to additional stress challenges, like oxidative stress. This proposal shifts the paradigm of research on auditory hair cell (HC) degeneration and regeneration by showing that a mutant protein induces endoplasmic reticulum (ER) stress, leading to hair cell loss. These studies will provide new targets to explore protective therapies for USH/DFNB12 and age-related hearing loss.

Public Health Relevance

More than 28 million Americans and 360 million people worldwide have hearing loss. Understanding molecular pathway and determining the molecular pathogenesis of hearing loss in genetically defined mouse models is the key for discovery of therapeutic targets that prevent cochlear hair cell death and hearing loss.

National Institute of Health (NIH)
National Institute on Deafness and Other Communication Disorders (NIDCD)
Research Project (R01)
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Special Emphasis Panel (ZRG1-IFCN-B (02))
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Watson, Bracie
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Case Western Reserve University
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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 :
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