Regulation of outer hair cell electromotility and noise-induced hearing loss

Summary

Principal Investigator: Gregory I Frolenkov
Abstract: DESCRIPTION (provided by applicant): 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.
Funding Period: 2009-02-18 - 2015-01-31
more information: NIH RePORT

Top Publications

  1. pmc Actin-bundling protein TRIOBP forms resilient rootlets of hair cell stereocilia essential for hearing
    Shin ichiro Kitajiri
    Laboratory of Molecular Genetics, National Institute on Deafness and Other Communication Disorders, National Institutes of Health, Rockville, MD 20850, USA
    Cell 141:786-98. 2010
  2. pmc TRPA1-mediated accumulation of aminoglycosides in mouse cochlear outer hair cells
    Ruben S Stepanyan
    Department of Physiology, University of Kentucky, Lexington, KY 40536 0298, USA
    J Assoc Res Otolaryngol 12:729-40. 2011
  3. pmc Fibroblast growth factor receptor 3 regulates microtubule formation and cell surface mechanical properties in the developing organ of Corti
    Katherine B Szarama
    Auditory Mechanics Section, Laboratory of Cellular Biology, National Institute on Deafness and Other Communication Disorders, National Institutes of Health, Bethesda, MD, USA
    Bioarchitecture 2:214-9. 2012
  4. pmc Tricellulin deficiency affects tight junction architecture and cochlear hair cells
    Gowri Nayak
    Laboratory of Molecular Genetics, Division of Pediatric Otolaryngology Head and Neck Surgery, Cincinnati Children s Hospital Research Foundation, Cincinnati, Ohio 45229, USA
    J Clin Invest 123:4036-49. 2013
  5. pmc Usher proteins in inner ear structure and function
    Zubair M Ahmed
    Division of Pediatric Ophthalmology, Cincinnati Children s Hospital Medical Center, University of Cincinnati, Ohio
    Physiol Genomics 45:987-9. 2013

Detail Information

Publications6

  1. pmc Actin-bundling protein TRIOBP forms resilient rootlets of hair cell stereocilia essential for hearing
    Shin ichiro Kitajiri
    Laboratory of Molecular Genetics, National Institute on Deafness and Other Communication Disorders, National Institutes of Health, Rockville, MD 20850, USA
    Cell 141:786-98. 2010
    ..Thus, F-actin bundling by TRIOBP provides durability and rigidity for normal mechanosensitivity of stereocilia and may contribute to resilient cytoskeletal structures elsewhere...
  2. pmc TRPA1-mediated accumulation of aminoglycosides in mouse cochlear outer hair cells
    Ruben S Stepanyan
    Department of Physiology, University of Kentucky, Lexington, KY 40536 0298, USA
    J Assoc Res Otolaryngol 12:729-40. 2011
    ..We concluded that TRPA1 channels may provide a novel pathway for the entry of aminoglycosides into OHCs...
  3. pmc Fibroblast growth factor receptor 3 regulates microtubule formation and cell surface mechanical properties in the developing organ of Corti
    Katherine B Szarama
    Auditory Mechanics Section, Laboratory of Cellular Biology, National Institute on Deafness and Other Communication Disorders, National Institutes of Health, Bethesda, MD, USA
    Bioarchitecture 2:214-9. 2012
    ..We conclude that microtubule formation is a major downstream effector of Fgf-receptor 3, and suggest this pathway impacts the formation of fluid spaces in the organ of Corti...
  4. pmc Tricellulin deficiency affects tight junction architecture and cochlear hair cells
    Gowri Nayak
    Laboratory of Molecular Genetics, Division of Pediatric Otolaryngology Head and Neck Surgery, Cincinnati Children s Hospital Research Foundation, Cincinnati, Ohio 45229, USA
    J Clin Invest 123:4036-49. 2013
    ..Finally, comprehensive phenotypic screening showed a broader pathological phenotype in the mutant mice, which highlights the non-redundant roles played by tricellulin. ..
  5. pmc Usher proteins in inner ear structure and function
    Zubair M Ahmed
    Division of Pediatric Ophthalmology, Cincinnati Children s Hospital Medical Center, University of Cincinnati, Ohio
    Physiol Genomics 45:987-9. 2013
    ..Therefore, elucidation of the functions of USH proteins in the stereocilia is a prerequisite to understanding the exact mechanisms of MET. ..

Research Grants30

  1. Afferent synaptic transmission in the mammalian cochlea
    Elisabeth Glowatzki; Fiscal Year: 2013
    ..Our results will support studies that aim to model how auditory nerve activity is generated. These approaches can provide a future basis for better cochlear implant design. ..
  2. GENETIC ANALYSIS OF MAMMALIAN HEARING SENSITIVITY
    Jian Zuo; Fiscal Year: 2013
    ..Our studies will contribute greatly to our understanding of cochlear amplification and the pathophysiology of deafness caused by a variety of genetic and environmental factors. ..
  3. INTRACELLULAR CALCIUM IN HAIR CELLS
    Robert Fettiplace; Fiscal Year: 2013
    ..We hypothesize that calcium overloading leading to mitochondrial dysfunction is a major route to cell damage. ..
  4. Hearing Preservation for Noise or Cochlear Implantation: Mechanisms &Treatments
    Richard A Altschuler; Fiscal Year: 2013
    ....
  5. Investigating the role of CaBP1 in KCNQ4 channel modulation
    KEITH ERIC BRYAN; Fiscal Year: 2013
    ..My proposed work will provide valuable new insight into how CaBP1, a member of the CaM-like Ca2+ binding proteins, modulates KCNQ channel activity. ..
  6. Patterning the tonotopic axis of the cochlea
    Benjamin R Thiede; Fiscal Year: 2013
    ..Finally, I aim to modulate candidate signaling pathways in vitro and in ovo to determine whether such manipulations disrupt normal patterning of HC phenotypes along the longitudinal axis of the cochlea. ..
  7. 3-D optical imaging of the in vivo organ of Corti motion at a sub-nanometer scale
    Alfred L Nuttall; Fiscal Year: 2013
    ....