Excessively loud sounds and noise are among the leading causes of deafness and hearing impairment in the US. Acoustic over-stimulation is likely to activate multiple physiological mechanisms, most of which are poorly understood. Perhaps the first process that would be shut down in the face of acoustic over-stimulation is the cochlear amplification of sound-induced vibrations. Prestin, a unique plasma membrane molecular motor of the outer hair cells, is critical for the cochlear amplification. Although regulation of important cellular functions via signaling pathways is a fundamental property of the cells, a signaling pathway that would "shut down" the operation of prestin is still unknown. Our preliminary data show that direct activation of TRPA1 channels by specific agonists inhibits the motor activity of prestin in the outer hair cells. This inhibition is not observed in mice lacking the TRPA1 channels (Trpa1-/-). Since TRPA1 could be a downstream target of a variety of second-messenger systems, TRPA1-mediated inhibition of prestin may represent a general mechanism regulating cochlear amplification during various stresses, including acoustic over-stimulation. Consistent with this idea, our preliminary data show that moderate noise exposure results in a significantly larger elevation of hearing thresholds in Trpa1-/- mice as compared to wild type (Trpa1+/+) littermates. Although the signaling pathways that control TRPA1 in outer hair cells have yet to be identified, we found that extracellular ATP can inhibit prestin motor activity in Trpa1+/+ but not in Trpa1-/- mice. The goal of this project is to determine how TRPA1 channels participate in the protection of the cochlea from over- stimulation. This study will test the following central hypothesis: The cochlea is protected from acoustic over-stimulation by activation of TRPA1 channels and inhibition of prestin motor activity, a previously unknown mechanism that can be activated via metabotropic ATP receptors. The proposed study will determine: 1) specific intracochlear processes that are affected by a TRPA1 deficiency;2) the mechanism of TRPA1 activation in outer hair cells;3) the mechanism of TRPA1-mediated inhibition of outer hair cell electromotility. Identification of the cellular processes and key molecules regulating outer hair cell electromotility at high sound intensities will open a new avenue of research in the field of noise-induced hearing loss. It may also lead to pharmacological interventions that would prevent damage of the cochlea through the enhancement of natural protection mechanisms. Finally, the genes encoding the proteins involved in this novel mechanism of cochlear regulation would represent attractive candidates to screen for genetic variants that are associated with susceptibility or resistance to noise-induced and perhaps other types of hearing loss. This research is relevant to public health because it investigates a previously unknown mechanism that protects the inner ear from damage due to acoustic over-stimulation. The experimental results should help scientists develop treatments for the noise-induced hearing loss, which is one of the most common causes of deafness and hearing impairment.

Public Health Relevance

This research is relevant to public health because it investigates previously unknown mechanism that protects the inner ear from damage due to acoustic over-stimulation. The experimental results should help scientist to develop treatments for the noise-induced hearing loss, which is one of the most common cause of deafness and hearing impairment.

Agency
National Institute of Health (NIH)
Institute
National Institute on Deafness and Other Communication Disorders (NIDCD)
Type
Research Project (R01)
Project #
5R01DC009434-04
Application #
8213476
Study Section
Auditory System Study Section (AUD)
Program Officer
Freeman, Nancy
Project Start
2009-02-18
Project End
2014-01-31
Budget Start
2012-02-01
Budget End
2013-01-31
Support Year
4
Fiscal Year
2012
Total Cost
$268,504
Indirect Cost
$85,225
Name
University of Kentucky
Department
Physiology
Type
Schools of Medicine
DUNS #
939017877
City
Lexington
State
KY
Country
United States
Zip Code
40506
Ahmed, Zubair M; Frolenkov, Gregory I; Riazuddin, Saima (2013) Usher proteins in inner ear structure and function. Physiol Genomics 45:987-9
Nayak, Gowri; Lee, Sue I; Yousaf, Rizwan et al. (2013) Tricellulin deficiency affects tight junction architecture and cochlear hair cells. J Clin Invest 123:4036-49
Stepanyan, Ruben S; Indzhykulian, Artur A; VĂ©lez-Ortega, A Catalina et al. (2011) TRPA1-mediated accumulation of aminoglycosides in mouse cochlear outer hair cells. J Assoc Res Otolaryngol 12:729-40
Kitajiri, Shin-ichiro; Sakamoto, Takeshi; Belyantseva, Inna A et al. (2010) Actin-bundling protein TRIOBP forms resilient rootlets of hair cell stereocilia essential for hearing. Cell 141:786-98