Modulation of Cochlear Tuning

描述（由申请人提供）：本研究计划的目的是了解耳蜗隔的被动和主动调谐特性之间的关系，并开发可用于改变耳蜗频率图的技术。哺乳动物的耳蜗是根据耳蜗隔的被动力学的系统性变化而调谐的。外毛细胞（OHC）电运动性是耳蜗隔层的一个积极组成部分，它为行波增加能量，使耳蜗调谐变得更尖锐和移位，并赋予精细的听觉灵敏度和频率选择性。我们假设改变耳蜗隔层的生物力学特性可以调节耳蜗调谐的清晰度、灵敏度和共振频率图。在本研究中，将利用豚鼠耳蜗进行体内和体外实验，以操纵耳蜗隔板的被动和主动成分。为了调节被动力学，基底膜将被磁场控制的刚性探针或顺磁珠置换，或被激光光凝硬化。为了调节主动机制，将通过淋巴周围灌注给药来靶向OHC内正常电运动性所必需的特定部位。要调节的目标包括OHC膨胀压力、细胞骨架刚度、膜流动性、阴离子浓度和prestin马达蛋白。基底膜运动将用激光多普勒振动仪测量。其他监测耳蜗功能的指标包括复合动作电位、畸变产物耳声发射、耳蜗传声器和内淋巴电位。这些数据将与颞骨的组织学研究和计算机建模分析相结合，以了解实验操作的影响。除了进行这项研究之外，候选人还将利用这段时间和这笔资助发展成为一名独立的临床科学家。这将包括结构化的教学活动以及与两位导师和几位合作者的密切互动。该候选人的长期目标是扩展这条转化研究线，以开发针对噪声诱导和年龄相关的感音神经性听力损失患者的治疗干预措施。

DESCRIPTION (provided by applicant): The aim of this research proposal is to understand the relationship between the passive and active tuning properties of the cochlear partition and to develop techniques that can be used to change the cochlear frequency map. The mammalian cochlea is tuned tonotopically based upon systematic changes in the passive mechanics of the cochlear partition. Outer hair cell (OHC) electromotility is an active component of the cochlear partition that adds energy to the traveling wave, sharpens and shifts cochlear tuning, and imparts exquisite hearing sensitivity and frequency selectivity. We hypothesize that changing the biomechanical properties of the cochlear partition will modulate the sharpness, sensitivity, and resonant frequency map of cochlear tuning. In the proposed research, in vivo and in vitro experiments designed to manipulate both the passive and the active components of the cochlear partition will be performed using the guinea pig cochlea. In order to modulate the passive mechanics, the basilar membrane will be displaced either by a stiffprobe or paramagnetic beads controlled by a magnetic field, or stiffened by laser photocoagulation. In order to modulate the active mechanics, specific sites within the OHC necessary for normal electromotility will be targeted using drugs administered via perilymphatic perfusion. The targets to be modulated include OHC turgor pressure, cytoskeletal stiffness, membrane fluidity, anion concentration, and the prestin motor protein. Basilar membrane motion will be measured using a laser doppler vibrometer. Other measures of cochlear function to be monitored include the compound action potential, distortion product otoacoustic emissions, the cochlear microphonic, and the endolymphatic potential. These data will be combined with histologic study of the temporal bones and computer modeling analysis to understand the impact of experimental manipulations. In addition to pursuing this research, the candidate will use this time and funding provided by this grant to develop into an independent clinician-scientist. This will involve both structured didactic activities as well as close interactions with two mentors and several collaborators. The long-term goal of the candidate is to extend this line of translational research to develop therapeutic interventions for patients with noise-induced and age-related sensorineural hearing loss.