C57BL/6J (B6) mice have a well-characterized age-related hearing loss (AHL) phenotype. A recent study has shown that this loss is only partially caused by mutations in the Cadherin 23 (Cdh23) gene which encodes the tip link protein CDH23 (Kane et al., 2011). In mice and in humans, mutations in Cdh23 are exacerbated by mutations in the plasma membrane Ca2+ ATPase 2 (PMCA2) protein, which regulates intracellular Ca2+ levels (Noben-Trauth et al., 1997 and Schultz et al., 2007). This interaction is likely due to the necessity of Ca2+ in maintaining the structural integrity of CDH23 (Sotomayor et al., 2010). There are no mutations in the B6 Atp2b2 gene, which encodes PMCA2. However, two discreet measures of gene expression show that there is down-regulation of Atp2b2 transcript in B6 compared to the good-hearing strain CBA/CaJ (CBA). Studies of the deafwaddler mutations in Atp2b2 demonstrate that the auditory system is highly sensitive to small changes in Atp2b2. These mice exhibit changes in hearing sensitivity that can be correlated to changes in regulation, function and expression of Atp2b2 (McCullough and Tempel, 2004; Watson and Tempel, 2013). All of this evidence suggests that the down-regulation of Atp2b2 in B6 is a likely contributor to the age-related hearing loss phenotype in these mice. As there are no mutations in the protein coding region of Atp2b2 but changes in transcript expression, transcriptional processes are likely involved in the down-regulation of Atp2b2 in B6. Recent experiments in the Tempel lab have confirmed the presence of a long intergenic non-coding RNA (lincRNA-83) that is in the intronic regions of the mouse Atp2b2 gene. Expression studies indicate that this gene is misregulated in the brainstem and the cochlea of B6 mice. Importantly, lincRNAs are emerging as key players in transcriptional regulation of nearby genes (Wang and Chang, 2011). The over-arching hypothesis in this proposal is that Atp2b2 misregulation in B6 contributes to AHL in this strain. We propose two aims to better understand the: 1) degree of expression differences between B6 and CBA, and 2) the extent to which non-coding RNAs regulate the Atp2b2 gene.

Public Health Relevance

We are studying the genetic mechanisms that contribute to hearing loss and deafness. This research allows scientists to identify potential targets for pharmacological therapies to treat hearing loss. The studies in this proposal investigate the regulation of PMCA2, a protein that is critical for regulating calcium in the peripheral auditory system. Genetic mutations of PMCA2 have been linked to hearing loss and deafness.

Agency
National Institute of Health (NIH)
Institute
National Institute on Deafness and Other Communication Disorders (NIDCD)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21DC014864-01
Application #
8974974
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Watson, Bracie
Project Start
2015-07-01
Project End
2017-06-30
Budget Start
2015-07-01
Budget End
2016-06-30
Support Year
1
Fiscal Year
2015
Total Cost
Indirect Cost
Name
University of Washington
Department
Otolaryngology
Type
Schools of Medicine
DUNS #
605799469
City
Seattle
State
WA
Country
United States
Zip Code
98195