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: 8413775
• 负责人: Gregory I Frolenkov
• 金额: $ 25.51万
• 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 2015-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8413775
• 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，其中大多数尚不清楚。也许面对声学过度刺激时，第一个被关闭的过程是耳蜗对声音引起的振动的放大。Prestin是一种独特的外毛细胞质膜分子马达，对耳蜗放大至关重要。尽管通过信号通路调节重要的细胞功能是细胞的基本特性，但能够“关闭”prestin作用的信号通路尚不清楚。我们的初步数据表明，通过特异性激动剂直接激活TRPA1通道可抑制外毛细胞中prestin的运动活性。在缺乏TRPA1通道（TRPA1 -/-）的小鼠中没有观察到这种抑制作用。由于TRPA1可能是多种第二信使系统的下游靶点，TRPA1介导的prestin抑制可能代表了在各种应激（包括声学过度刺激）下调节耳蜗放大的一般机制。与这一观点一致的是，我们的初步数据显示，与野生型（Trpa1+/+）的幼崽相比，适度的噪音暴露导致Trpa1-/-小鼠的听力阈值显著升高。虽然控制外毛细胞TRPA1的信号通路尚未确定，但我们发现细胞外ATP可以抑制TRPA1 +/+小鼠的prestin运动活性，而在TRPA1 -/-小鼠中则没有。该项目的目的是确定TRPA1通道如何参与保护耳蜗免受过度刺激。本研究将验证以下中心假设：耳蜗通过激活TRPA1通道和抑制prestin运动活性来保护耳蜗免受声学过度刺激，这是一种以前未知的机制，可以通过代谢性ATP受体激活。拟议的研究将确定：1)受TRPA1缺乏影响的特定耳蜗内过程；2)外毛细胞中TRPA1的激活机制；3) trpa1介导的外毛细胞电动力抑制机制。识别高声强下外毛细胞电运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新的途径。这也可能导致药物干预，通过增强自然保护机制来防止耳蜗损伤。最后，编码这种新的耳蜗调节机制所涉及的蛋白质的基因，将成为筛选与噪音诱发或其他类型听力损失相关的遗传变异的有吸引力的候选者。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，该机制保护内耳免受过度刺激造成的损伤。实验结果将有助于科学家开发出治疗噪音性听力损失的方法。噪音性听力损失是耳聋和听力障碍的最常见原因之一。

项目成果

Fibroblast growth factor receptor 3 regulates microtubule formation and cell surface mechanical properties in the developing organ of Corti.

• DOI: 10.4161/bioa.22332
• 发表时间: 2012-11
• 期刊: Bioarchitecture
• 作者: Szarama KB;Stepanyan R;Petralia RS;Gavara N;Frolenkov GI;Kelley MW;Chadwick RS
• 通讯作者: Chadwick RS

TRPA1 activation in non-sensory supporting cells contributes to regulation of cochlear sensitivity after acoustic trauma.

• DOI: 10.1038/s41467-023-39589-w
• 发表时间: 2023-06-30
• 期刊: NATURE COMMUNICATIONS
• 影响因子: 16.6
• 作者: Velez-Ortega, A. Catalina;Stepanyan, Ruben;Edelmann, Stephanie E.;Torres-Gallego, Sara;Park, Channy;Marinkova, Desislava A.;Nowacki, Joshua S.;Sinha, Ghanshyam P.;Frolenkov, Gregory I.
• 通讯作者: Frolenkov, Gregory I.