Acoustic and electrical hearing after Atoh1 treatment

Atoh1 治疗后的声学和电学听力

• 批准号: 7901267
• 负责人: BRYAN E PFINGST
• 金额: $ 12.51万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-14 至 2011-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7901267
• 关键词: Acoustic Nerve; Acoustic Stimulation; Acoustics; Action Potentials; Adenovirus Vector; Aminoglycosides; Animals; Apical; Area; Audiometry; Auditory; Auditory Brainstem Responses; Back; Behavioral; Cavia; Cell Survival; Cells; Clinical; Cochlea; Cochlear Implants; Cochlear implant procedure; Combined Modality Therapy; Complement; Control Animal; Control Groups; Cues; Data; Detection; Development; Differential Threshold; Discrimination; Ear; Electric Stimulation; Esthesia; Ethacrynic Acid; Evoked Potentials, Auditory, Brain Stem; Exhibits; Frequencies; Genes; Hair Cells; Health; Hearing; Histology; Implant; Injection of therapeutic agent; Inner Hair Cells; Kanamycin; Laboratories; Lead; Left; Lesion; Location; Measures; Morphology; Nature; Neurons; Noise; Organ of Corti; Performance; Peripheral; Pharmaceutical Preparations; Physiological; Population; Positioning Attribute; Procedures; Process; Psychophysics; Psychophysiology; Recovery; Reflex action; Relative (related person); Replacement Therapy; Risk; Sensorineural Hearing Loss; Site; Stereocilium; Stimulus; System; Techniques; Testing; Time; Tissues; Viral Vector; Visual; Work; auditory pathway; base; combination gene therapy; comparison group; ganglion cell; gene therapy; hair cell regeneration; implantation; improved; in vivo; nerve supply; otoacoustic emission; relating to nervous system; research study; response; restoration; spiral ganglion; tectorial membrane; visual stimulus

We have recently demonstrated that new inner hair cells (IHCs) are generated in the mammalian organ of Corti following gene therapy. Specifically, the experiments involve in vivo inoculation of an adenovirus vector with the Atohl gene insert (M.Atohl) into the mature predeafened guinea pig cochlea. We have also demonstrated that the new hair cells can attract neurons. Predeafened ears treated with Atohl exhibit partial restoration of function as determined by Preyer's reflex and acoustically-evoked auditory brainstem response (ABR) thresholds. In the current application we propose to use animal- psychophysics techniques and physiological measures to define the nature and extent of the restored acoustic hearing. We will also conduct experiments relevant to the use of this Atohl therapy in conjunction with cochlear implants. For the first two specific aims we will deafen guinea pigs with ototoxic drugs, treat them with Atohl and measure psychophysical detection (Aim 1) and discrimination (Aim 2) as well as ABRs and distortion product otoacoustic emissions (DPOAEs). In Aim 3, we will assess the interaction between M.Atohl inoculation, cochlear implantation, and electrical stimulation of the cochlear implant. In Aim 4 we will place a cochlear implant in the inoculated ear and assess psychophysical responses to electrical stimulation and electrically evoked compound action potentials (ECAPs) with and without restored IHCs. Controls with some surviving hair cells (i.e., animals that are implanted but not predeafened) will be used for comparison to animals with restored hair cells. The experiments we propose involve the use of techniques that are already in place in our laboratories. The work is backed by strong preliminary data, and represents an ideal combination of relatively low-risk with very high impact. The proposed experiments will enhance our understanding of the functional significance of hair cell regeneration in the mammalian cochlea and contribute to the development of a clinical therapy for sensorineural deafness involving the combined use of cochlear implantation with cell replacement therapy.

我们最近证明，哺乳动物中会产生新的内毛细胞（IHC） 基因治疗后的柯蒂氏器。具体来说，该实验涉及体内接种 将带有 Atohl 基因插入 (M.Atohl) 的腺病毒载体插入成熟的预聋豚鼠耳蜗中。 我们还证明新的毛细胞可以吸引神经元。耳聋前期的治疗方法 根据 Preyer 反射和声诱发确定，Atohl 表现出部分功能恢复 听觉脑干反应（ABR）阈值。在当前的应用中，我们建议使用动物 心理物理学技术和生理测量来定义恢复的性质和程度 听觉。我们还将进行与使用 Atohl 疗法相关的实验 与人工耳蜗结合。 对于前两个具体目标，我们将用耳毒性药物使豚鼠耳聋，并用 Atohl 治疗它们 并测量心理物理检测（目标 1）和歧视（目标 2）以及 ABR 和扭曲 产品耳声发射 (DPOAE)。在目标 3 中，我们将评估 M.Atohl 之间的相互作用 接种、人工耳蜗植入以及人工耳蜗的电刺激。在目标 4 中，我们将 在接种过的耳朵中放置人工耳蜗并评估对电的心理物理反应 有或没有恢复 IHC 的刺激和电诱发复合动作电位 (ECAP)。 将使用一些幸存毛细胞的对照（即植入但未预耳聋的动物） 与毛细胞恢复的动物进行比较。 我们建议的实验涉及使用我们已经采用的技术 实验室。这项工作有强有力的初步数据支持，代表了以下方面的理想组合： 风险相对较低，但影响非常大。所提出的实验将增强我们对 哺乳动物耳蜗毛细胞再生的功能意义并有助于 联合使用人工耳蜗治疗感音神经性耳聋的临床疗法的开发 植入细胞替代疗法。