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: 8015254
• 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/8015254
• 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）：在美国，过大的声音和噪音是导致耳聋和听力障碍的主要原因之一。声学过度刺激可能激活多种生理机制，其中大多数机制知之甚少。也许第一个在声音过度刺激面前被关闭的过程是耳蜗对声音引起的振动的放大。普雷斯廷是耳蜗外毛细胞特有的质膜分子马达，在耳蜗放大中起着关键作用。虽然通过信号通路调节重要的细胞功能是细胞的基本特性，但是能够“关闭”普雷斯廷的操作的信号通路仍然是未知的。我们的初步数据表明，TRPA 1通道的直接激活特异性激动剂抑制普雷斯廷在外毛细胞的运动活动。在缺乏TRPA 1通道（Trpa 1-/-）的小鼠中未观察到这种抑制。由于TRPA 1可能是多种第二信使系统的下游靶点，因此TRPA 1介导的普雷斯廷抑制可能代表了在各种应激（包括声学过度刺激）期间调节耳蜗放大的一般机制。与这一想法一致，我们的初步数据表明，适度的噪声暴露的结果在一个显着更大的升高Trpa 1-/-小鼠的听力阈值相比，野生型（Trpa 1 +/+）同窝仔。虽然控制外毛细胞中TRPA 1的信号通路尚未确定，但我们发现细胞外ATP可以抑制Trpa 1 +/+小鼠的普雷斯廷运动活性，但不能抑制Trpa 1-/-小鼠的运动活性。该项目的目标是确定TRPA 1通道如何参与保护耳蜗免受过度刺激。本研究将检验以下中心假设：通过激活TRPA 1通道和抑制普雷斯廷运动活动，保护耳蜗免受声学过度刺激，这是一种以前未知的机制，可通过代谢型ATP受体激活。拟议的研究将确定：1）受TRPA 1缺陷影响的特定脑内过程; 2）TRPA 1在外毛细胞中激活的机制; 3）TRPA 1介导的抑制外毛细胞电活动的机制。确定在高声强下调节外毛细胞电活动的细胞过程和关键分子将为噪声性听力损失领域的研究开辟一条新的途径。它还可能导致药理干预，通过增强自然保护机制来防止耳蜗损伤。最后，编码参与耳蜗调节的这种新机制的蛋白质的基因将代表有吸引力的候选人，以筛选与噪声诱导的听力损失和其他类型的听力损失的易感性或抗性相关的遗传变异。这项研究与公共卫生有关，因为它调查了一种以前未知的机制，可以保护内耳免受声学过度刺激造成的损伤。实验结果应该有助于科学家开发治疗噪音引起的听力损失的方法，这是耳聋和听力障碍的最常见原因之一。