Repair of mechano-electrical transduction in mammalian auditory hair cells

Grants and Contracts Details

Description

The goal of this project is to explore the mechanisms of mechanical damage and subsequent repair in mechanotransduction machinery of the mammalian auditory hair cells. It is widely presumed that the mechanosensory machinery in the stereocilia bundles of the inner ear hair cells is very vulnerable to intense mechanical stimulation. Yet, we still do not know what exactly is damaged within transduction machinery and whether these damages can be repaired by the cell. Meanwhile, these damages may represent a significant component in noise-induced hearing loss. More importantly, the ability of the hair cell to repair these damages may determine whether the noise-induced temporary shift of hearing thresholds would recover or progress into the permanent hearing loss. Interestingly, damage to the actin core of stereocilia is known as a hallmark of the permanent noise-induced hearing loss for more than two decades. However, very little is known on how this damage develops or is repaired. We have recently initiated a systematic study of the effects of mechanical overstimulation on the mechano-electrical transduction and the ultrastructure of stereocilia bundle in young postnatal cochlear hair cells. A first anticipated effect of overstimulation is the loss of tip links that are known to regenerate. Using a novel immunogold scanning electron microscopy technique, we have recently discovered that the tip link regeneration may involve a two-step molecular remodeling that includes formation of the temporary links with protocadherin-15 at both ends of the link and then replacing them with the more mature links containing protocadherin-15 and cadherin-23. Specific Aim 1 of the proposed project will determine whether a similar molecular remodeling occurs during tip link regeneration after mechanical overstimulation. We have also found that, surprisingly, mechanical overstimulation does not abolish all tip links in the cochlear hair cells; many of them withstand overstimulation. The recordings of mechanotransducer currents indicated that these tip links are likely “saved” due to dramatic loss of the resting tension within the transduction machinery. Using fast Ca2+ imaging in individual stereocilia, we found that the hair cell is able to re-tension the transduction apparatus via a novel, extremely slow Ca2+- dependent process. Specific Aim 2 of the proposed project explores the structural and molecular mechanisms of this phenomenon. Finally, we found that overstimulation causes small, nanometer- scale gaps in the actin core of stereocilia, similar to the ones that we previously observed in degenerating stereocilia lacking gamma-actin. Specific Aim 3 will explore whether the hair cell can repair these gaps and whether this potential repair mechanism depends on gamma-actin. We believe that our study is a long-awaited step in exploring the potential mechanisms of the noise-induced hearing loss. For many years, the field concentrated on the mechanisms of hair cell survival after acoustic trauma. Only few studies explored the upstream effects of the overstimulation on the ultrastructure of the hair cell stereocilia bundle. Even less was known about the effects of mechanical overstimulation on the mechano-electrical transduction. The proposed project fills this important gap in our knowledge.
StatusFinished
Effective start/end date2/15/157/31/21

Funding

  • National Institute on Deafness & Other Communications: $1,962,789.00

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