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

外毛细胞电动性和噪声性听力损失的调节

• 批准号: 8213476
• 负责人: Gregory I Frolenkov
• 金额: $ 26.85万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-02-18 至 2014-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8213476
• 关键词: 4 hydroxynonenal; ATP Receptors; Acoustic Nerve; Acoustics; Action Potentials; Affect; Agonist; Calmodulin; Cell membrane; Cell physiology; Cells; Cochlea; Cyclic GMP; Data; Evoked Potentials, Auditory, Brain Stem; GTP-Binding Proteins; Genes; Goals; Gramicidin; Hair Cells; Hearing; Image; In Situ; In Vitro; Intervention; Labyrinth; Lead; Lipid Peroxidation; Mediating; Methods; Modification; Molecular Motors; Motor; Motor Activity; Mus; Noise; Noise-Induced Hearing Loss; Organ of Corti; Outer Hair Cells; Pathway interactions; Physiological; Predisposition; Preparation; Process; Property; Proteins; Public Health; Regulation; Research; Resistance; Scientist; Second Messenger Systems; Sensory; Signal Pathway; Signal Transduction Pathway; Stress; TRPA1 Channel; Techniques; Testing; base; cell type; deafness; extracellular; flash photolysis; genetic variant; hearing impairment; in vivo; mouse ANKTM1 protein; novel; operation; otoacoustic emission; prevent; rat Pres protein; response; sound; vibration

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.

描述（由申请人提供）：美国的耳聋和听力障碍的主要原因之一。声学过度刺激可能会激活多种生理机制，其中大多数理解很少。面对声学过度刺激的第一个过程可能是声音引起的振动的人工耳蜗放大。 Prestin是外毛细胞的独特质膜分子运动，对于人工耳蜗放大至关重要。尽管通过信号通路对重要的细胞函数进行调节是细胞的基本特性，但仍未知Prestin的信号通路“关闭” Prestin的操作。我们的初步数据表明，特定激动剂通过特定激动剂直接激活TRPA1通道会抑制Prestin在外毛细胞中的运动活性。在缺乏TRPA1通道（TRPA1 - / - ）的小鼠中未观察到这种抑制作用。由于TRPA1可能是多种第二通间机系统的下游靶标，因此TRPA1介导的Prestin抑制可能代表了调节各种应力（包括声音过度刺激）的一般机制。与这个想法一致，我们的初步数据表明，与野生型（TRPA1+/+）同窝仔相比，中等噪声暴露会导致TRPA1 - / - 小鼠中听力阈值的升高。尽管尚未确定控制外毛细胞中TRPA1的信号通路，但我们发现细胞外ATP可以抑制TRPA1+/+中的Prestin运动活性，但在TRPA1-/ - 小鼠中不能抑制Prestin运动活性。该项目的目的是确定TRPA1通道如何参与对耳蜗过度刺激的保护。这项研究将检验以下中心假设：通过激活TRPA1通道和抑制Prestin运动活性，该耳蜗可免受声学过度刺激，这是一种以前未知的机制，可以通过代替ATP受体激活。拟议的研究将确定：1）受TRPA1缺乏影响的特定特定的运动内过程； 2）外毛细胞中TRPA1激活的机制； 3）TRPA1介导的外部毛细胞电动性的抑制作用的机制。在高声强度下调节外毛细胞电动性的细胞过程和关键分子的鉴定将在噪声引起的听力损失领域开设新的研究途径。这也可能导致药理学干预措施，从而通过增强自然保护机制来防止耳蜗损坏。最后，编码这种新型人工耳蜗机制所涉及的蛋白质的基因将代表有吸引力的候选者，以筛选与易感性或对噪声引起的和其他类型的听力丧失相关的遗传变异的遗传变异。这项研究与公共卫生有关，因为它研究了一种以前未知的机制，该机制可以保护内耳免受声学过度刺激而造成的损害。实验结果应有助于科学家开发噪声引起的听力损失的治疗方法，这是聋哑和听力障碍的最常见原因之一。