Role of tonic outer hair cell motility in cochlear amplification

强直外毛细胞运动在耳蜗放大中的作用

• 批准号: 10115442
• 负责人: James Braden Dewey
• 金额: $ 16.5万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-23 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10115442
• 关键词: Acoustic Stimulation; Address; Adult; Apical; Biological; Cells; Chemicals; Cochlea; Complex; Data; Defect; Dependence; Ear; Exhibits; Frequencies; Funding; Future; Generations; Geometry; Goals; Hearing; Impairment; Knock-in; Knowledge; Lateral; Length; Location; Measurement; Measures; Mechanics; Mediating; Membrane Potentials; Mentors; Motor; Mus; Mutant Strains Mice; Natural regeneration; Optical Coherence Tomography; Organ; Organ of Corti; Outer Hair Cells; Phase; Play; Positioning Attribute; Process; Prosthetic rehabilitation; Proteins; Receptor Cell; Research; Rest; Role; Sensory; Stimulus; Structure; Testing; Time; Work; base; career; cell injury; cell motility; design; hearing impairment; hearing restoration; improved; in vivo; mechanical properties; mechanotransduction; normal hearing; novel; rat Pres protein; receptor; regenerative; response; sound; vibration; voltage

PROJECT SUMMARY/ABSTRACT Mammalian hearing sensitivity depends on outer hair cells (OHCs), which change length and generate force to amplify sound-evoked vibrations within the cochlea. While it is often assumed that amplification depends on cycle-by-cycle OHC motility, the ability of this mechanism to operate at sufficiently high frequencies in vivo has been questioned, and exactly how OHCs interact with the surrounding organ of Corti structures to produce amplification remains unclear. Clarifying how OHCs work is critical to understanding and restoring what is missing in ears with OHC damage, which is a common cause of hearing loss. As a step toward this, the proposed work will determine whether, in addition to fast, cycle-by-cycle length changes, OHCs undergo sustained, tonic length changes during sound stimulation. Such tonic motility may play a vital, unrecognized role in the amplification process if it is associated with changes in the organ of Corti’s geometry and mechanical properties. The proposed work will specifically test the hypothesis that sound elicits tonic OHC motility via the same electromotile process that drives cycle-by-cycle motility, and that this tonic motility influences cochlear amplification via changes in the stiffness of the organ of Corti. This hypothesis will be tested by using an optical coherence tomography-based approach to measure vibrations from within the intact mouse cochlea in vivo. Aim 1 will fully characterize the tonic, sound-evoked deformations of the organ of Corti as a function of stimulus frequency and level. If the hypothesis is correct, the top and bottom of the OHC region will tonically move in opposite directions during sound stimulation. Aim 2 will determine whether this tonic motility requires prestin (the motor protein that underlies cycle-by-cycle OHC motility) and normal mechanotransduction, which is needed to produce the receptor potential that drives prestin. This will be tested by measuring vibrations in mutant mice with abnormal prestin or impaired mechanotransduction. If the hypothesis is true, tonic motility will be reduced or absent in these mice. Aim 3 will assess whether tonic OHC motility influences cochlear amplification via associated changes in organ of Corti stiffness. This will be tested by presenting a very low frequency tone to slowly modulate OHC length and stiffness, and assessing changes in the organ’s frequency response over time. If the hypothesis is correct, slow OHC length changes will be associated with specific shifts in the organ’s frequency response. Pursuit of these aims may reveal novel OHC mechanisms for adjusting the frequency-tuning and gain of cochlear amplification, and thus challenge the current view of how amplification works. Ultimately, the knowledge gained could inform the design of future, biologically-inspired rehabilitative prosthetics as well as regenerative approaches to restoring hearing.

项目总结/文摘