Modulation of Cochlear Tuning

耳蜗调谐的调制

• 批准号: 6862674
• 负责人: John S Oghalai
• 金额: $ 16.74万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-03-01 至 2009-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6862674
• 关键词: biomechanics; cochlea; cochlear microphonic potentials; computer simulation; ear hair cell; guinea pigs; hearing disorders; labyrinthine membrane; magnetic field; membrane potentials; otoacoustic emission; sound frequency; sound perception; vibration perception

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.

描述(由申请人提供)：本研究计划的目的是了解耳蜗区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。哺乳动物的耳蜗会根据耳蜗区被动力学的系统性变化进行音调调节。外毛细胞(OHC)电活动是耳蜗区的一种活跃成分，它为行波增加能量，锐化和改变耳蜗调谐，并赋予精致的听力灵敏度和频率选择性。我们假设，改变耳蜗区的生物力学特性将调制耳蜗调谐的锐度、灵敏度和共振频率图。在这项拟议的研究中，将使用豚鼠耳蜗进行体内和体外实验，以操纵耳蜗区的被动和主动成分。为了调制被动力学，基底膜将被磁场控制的刚性探头或顺磁珠移位，或通过激光光凝硬化。为了调节主动机制，OHC内正常电动所必需的特定部位将通过外淋巴灌流给药进行靶向治疗。需要调节的目标包括OHC膨压、细胞骨架硬度、膜流动性、阴离子浓度和Prestin马达蛋白。将使用激光多普勒振动仪测量基底膜的运动。需要监测的其他指标包括复合动作电位、失真产物耳声发射、耳蜗微音响和内淋巴电位。这些数据将与对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。除了从事这项研究外，候选人还将利用这段时间和这笔拨款提供的资金，发展成为一名独立的临床医生兼科学家。这将包括有组织的教学活动以及与两位导师和几位合作者的密切互动。候选人的长期目标是扩展这一翻译研究路线，为噪音引起的和年龄相关的感音神经性听力损失患者开发治疗干预措施。