Mouse, Man, and Machine: Combining Model Systems to Develop a Biomarker for Cochlear Deafferentation in Humans (Administrative Supplement)

小鼠、人和机器：结合模型系统开发人类耳蜗传入神经阻滞的生物标志物（行政补充）

• 批准号: 10681110
• 负责人: Naomi Bramhall
• 金额: $ 1.48万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-15 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10681110
• 关键词: Administrative Supplement; Affect; Aging; Animal Model; Auditory; Auditory Brainstem Responses; Biological Markers; Biological Models; Cochlea; Computer Models; Data; Deafferentation procedure; Development; Diagnosis; Diagnostic tests; Hearing Tests; Hearing problem; Histologic; Human; Hyperacusis; Individual; Inner Hair Cells; Knowledge; Lead; Measurement; Measures; Methods; Mission; Mus; Outer Hair Cells; Peripheral; Persons; Pharmacotherapy; Physiological; Prevalence; Prevention; Public Health; Reflex action; Research; Risk Factors; Speech Perception; Synapses; Testing; Tinnitus; Translations; United States National Institutes of Health; Work; base; cell injury; disability; ear muscle; ganglion cell; human model; human subject; individual patient; innovation; man; middle ear; noise exposure; otoacoustic emission; prevent; research clinical testing; response; spiral ganglion

Project Summary Clinical testing for peripheral auditory dysfunction focuses on the audiogram. However, many auditory perceptual deficits, such as tinnitus, hyperacusis, and difficulty with speech perception, cannot be fully explained by the audiogram. Cochlear deafferentation (i.e., loss of inner hair cells, spiral ganglion cells, or cochlear synapses), may contribute to these perceptual problems. However, there is currently no method for diagnosing deafferentation in living humans. This prevents us from determining the prevalence of deafferentation in humans, identifying deafferentation risk factors and perceptual consequences, or testing potential drug treatments. Several non-invasive physiological measures are sensitive to loss of cochlear synapses (a form of deafferentation) in animal models, including the auditory brainstem response (ABR), the envelope following response (EFR), and the middle ear muscle reflex (MEMR). However, it is unclear how cochlear gain loss (e.g., due to outer hair cell damage) impacts the relationship between deafferentation and these physiological measures, hindering translation to a diagnostic test for deafferentation. The overall objective of this proposal is to develop a computational model that can estimate deafferentation from non-invasive physiological measurements in humans with varying degrees of cochlear gain loss. The central hypothesis is that cochlear gain loss can be predicted from distortion product otoacoustic emissions (DPOAEs) and deafferentation can be predicted from a combination of ABR, EFR, and MEMR measurements. This hypothesis will be tested by pursuing four specific aims: 1) Expand a computational model of the auditory periphery (CMAP) to predict ABR, EFR, MEMR, and DPOAE responses in mice and humans based on both cochlear gain and afferent function, 2) Validate and refine the CMAP by collecting physiological and histological data from mouse, 3) Predict deafferentation in individual human subjects from physiological measurements by fitting the CMAP using Bayesian regression, and 4) Evaluate deafferentation predictions for their relationship with risk factors and predicted perceptual consequences of deafferentation. This approach is innovative because it extends prior work to animal and human models with both cochlear gain loss and deafferentation, uses computational modeling to bridge the gap between model systems, and combines multiple physiological measurements to predict deafferentation in individual human subjects. The proposed research is significant because we currently have no means of diagnosing deafferentation. Thus, the prevalence, associated risk factors, and perceptual impacts of this condition are unclear. This project is expected to result in a biomarker of deafferentation for individual patients that is based on their physiological measurements. This will enable us to identify peripheral auditory damage that is independent of cochlear gain loss. If the biomarker is correlated with risk factors such as noise exposure and auditory perceptual deficits such as speech perception difficulty, it will allow for the development of targeted treatments for auditory perceptual deficits and strategies for damage prevention.

项目摘要 外周听觉功能障碍的临床测试主要集中在听力图上。然而，许多听觉知觉 缺陷，如耳鸣、听觉亢进和言语感知困难，不能完全用 听力图。耳蜗失传入(即内毛细胞、螺旋神经节细胞或耳蜗突触的丧失)， 可能会导致这些知觉问题。然而，目前还没有诊断的方法 活人的去传入。这阻止了我们确定人类去传入的流行率， 识别去传入风险因素和知觉后果，或测试潜在的药物治疗。 几种非侵入性生理指标对耳蜗性突触的丢失(一种形式 在动物模型中)，包括听性脑干反应(ABR)，包络如下 反应(EFR)和中耳肌肉反射(MEMR)。然而，目前尚不清楚耳蜗增益损失(例如， 由于外毛细胞损伤)影响了去传入和这些生理的关系 措施，阻碍转化为去传入的诊断性测试。这项提议的总体目标是 开发一种可以估计非侵入性生理的去传入的计算模型 在具有不同程度耳蜗增益损失的人类中进行测量。中心假说是，耳蜗管 增益损失可以通过失真产物耳声发射(DPOAE)来预测，去传入可以 从ABR、EFR和MEMR测量的组合预测。这一假设将通过以下方式检验 追求四个具体目标：1)扩展听觉外周的计算模型(CMAP)以预测ABR， EFR、MEMR和DPOAE在小鼠和人类中的反应，基于耳蜗增益和传入功能，2) 通过收集小鼠的生理和组织学数据来验证和提炼CMAP，3)预测 通过对CMAP进行拟合，使个体受试者脱离生理测量的传入 贝叶斯回归，以及4)评估去传入预测与风险因素和 预测了去传入的知觉后果。这种方法是创新的，因为它扩展了以前的工作 对于既有耳蜗增益损失又有去传入的动物和人类模型，使用计算模型来 弥合模型系统之间的差距，并结合多种生理测量来预测 人类个体受试者的去传入。拟议的研究具有重要意义，因为我们目前有 没有诊断传入神经失控的方法。因此，患病率、相关的危险因素和知觉影响 这种情况的原因尚不清楚。该项目预计将导致个人去传入的生物标记物 这是根据他们的生理测量得出的。这将使我们能够识别周围的听觉 与耳蜗增益损失无关的损伤。如果生物标记物与噪声等风险因素相关 暴露和听觉知觉缺陷，如言语知觉困难，它将允许发展 有针对性地治疗听觉知觉缺陷和预防损害的战略。