Diagnosing outer hair cell health along the cochlear partition

描述(由申请人提供)： 感觉神经性听力损失是由于耳蜗和听神经内的各种结构受到损害而造成的。目前，基因和组织移植策略正在探索作为治疗听力损失的策略。不幸的是，目前还没有可用的诊断技术来隔离和区分耳蜗或听神经内受损的解剖位置(S)。确定病变部位的测试电池(S)将允许医生针对适当的解剖位置进行医疗干预。这项研究的长期目标是开发这些诊断测试。在这项建议中，R21阶段的目的是确定是否可以使用耳蜗微音器(CM)对嵌入高通噪声的低频音调做出反应，以量化沿耳蜗区丢失的外毛细胞的位置。外毛细胞的累积分布函数(CDF)是通过绘制特定掩蔽频率下被掩蔽的CM的幅度相对于未被掩蔽的幅度而获得的。我们假设CDF中平台的位置(或CDF中的某个其他变量或相应的概率密度函数)将与丢失的外毛细胞的位置有关。通过将CDF估计的缺失外毛细胞的位置与毛细胞损伤动物的解剖测量相关联来检验这一点。在临床人群中，外毛细胞可能存在，但功能异常。在R33阶段，我们根据毛细胞换能器的功能制定指标来确定存活的外毛细胞的健康状况。我们假设，1)换能器功能指数可以沿着耳蜗长获得，2)这些指数可以量化外毛细胞的健康状况，而不是对其他耳蜗结构造成损害。第一个目标是通过将一个指数的CDF平台位置与不同频率的暂时性听力损失动物的最大听力损失位置进行关联来测试第一个目标。第二个假设是通过比较外毛细胞和其他结构受损的动物组之间的指数来检验的。这项提案中的研究很可能适用于人类患者。目前，CM在美国和欧洲的听力学诊所被记录下来。未来优化刺激和记录位置的研究被设想为下一步开发诊断测试，以补充正在探索的治疗感音神经性听力损失的新医疗策略。 公共卫生相关性： 听力损失是由内耳和听神经内的各种解剖结构受损引起的。目前，科学和医学上都在朝着用基因和/或组织移植技术治疗听力损失的方向发展。不幸的是，没有诊断技术可以确定特定患者听力损失背后的结构的位置和健康状况。这项研究的目标是开发能够识别病变部位的诊断测试，以便医生可以针对适当的目标指导新的医疗治疗。

DESCRIPTION (provided by applicant): Sensorineural hearing loss results from damage to a variety of structures within the cochlea and auditory nerve. Presently, genetic and tissue transplantation strategies are being explored as therapeutic strategies for curing hearing loss. Unfortunately there are no available diagnostic techniques that isolate and distinguish the anatomic site(s) of damage within the cochlea or auditory nerve. A test battery that identifies the locus of lesion(s) will allow physicians to target the appropriate anatomic sites for medical intervention. The long-term goal of this research is to develop these diagnostic tests. In this proposal, the aim of the R21 phase is to determine if the cochlear microphonic (CM), in response to a low-frequency tone embedded in high-pass noise, can be used to quantify the location of missing outer hair cells along the cochlear partition. A cumulative distribution function (CDF) of outer hair cells is obtained by plotting the amplitude of the masked CM relative to the unmasked amplitude for specific masker frequencies. We hypothesize that the location of a plateau in the CDF (or some other variable in the CDF or corresponding probability density function) will relate to the location of missing outer hair cells. This is tested by correlating the location of missing outer hair cells estimated by the CDF with anatomic measurements in animals with hair cell lesions. In clinic populations, outer hair cells may be present but functioning abnormally. In the R33 phase we develop indices from hair cell transducer functions to determine the health of surviving outer hair cells. We hypothesize that 1) transducer function indices can be obtained along the length of the cochlea and 2) the indices can quantify outer hair cell health despite damage to other cochlear structures. The first goal is tested by correlating the location of the plateau of the CDF of an index with the location of maximum hearing loss in animals with temporary hearing loss at various frequencies. The second hypothesis is examined by comparing indices among groups of animals with lesions to outer hair cells and other structures. The studies in this proposal are likely to be translated to human patients. Presently, the CM is recorded in Audiologic clinics in the United States and Europe. Future studies optimizing stimuli and recording location are envisioned as the next step for developing diagnostic tests that compliment the new medical treatment strategies that are being explored to cure sensorineural hearing loss. PUBLIC HEALTH RELEVANCE: Hearing loss is caused by damage to a variety of anatomic structures both within the inner ear and auditory nerve. Presently, there is both a scientific and medical movement towards curing hearing loss with genetic and/or tissue transplantation techniques. Unfortunately there are no diagnostic techniques that can identify the location and health of the structures underlying hearing loss in a particular patient. The goal of this research is to develop diagnostic tests that identify the locus of lesion so that physicians can direct new medical treatments to the appropriate target.