Acoustic and electrical hearing after Atoh1 treatment

Atoh1 治疗后的声学和电学听力

• 批准号: 7096371
• 负责人: BRYAN E PFINGST
• 金额: $ 26.04万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-04-01 至 2011-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7096371
• 关键词: cochlea; cochlear implants; guinea pigs; hair; hearing; implant; innervation

DESCRIPTION (provided by applicant): 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 Atoh1 gene insert (Ad.Atoh1) into the mature predeafened guinea pig cochlea. We have also demonstrated that the new hair cells can attract neurons. Predeafened ears treated with Atoh1 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 Atoh1 therapy in conjunction with cochlear implants. For the first two specific aims we will deafen guinea pigs with ototoxic drugs, treat them with Atohl1 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 Ad.Atoh1 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.

描述（由申请人提供）：我们最近证明，在基因治疗后，在哺乳动物的Corti器官中产生了新的内毛细胞（IHCs）。具体而言，该实验涉及将带有Atoh1基因插入物（Ad.Atoh1）的腺病毒载体体内接种到成熟的预聋豚鼠耳蜗中。我们也证明了新的毛细胞可以吸引神经元。经Atoh1治疗的耳聋表现出部分功能恢复，这是由Preyer反射和声诱发听觉脑干反应（ABR）阈值决定的。在目前的应用中，我们建议使用动物心理物理学技术和生理学方法来定义听觉恢复的性质和程度。我们还将进行与使用这种Atoh1疗法结合人工耳蜗植入相关的实验。对于前两个具体目标，我们将用耳毒性药物致聋豚鼠，用atoh1治疗它们，并测量心理物理检测（Aim 1）和辨别（Aim 2）以及abr和失真产物耳声发射（dpoae）。在目标3中，我们将评估Ad和Ad之间的相互作用。人工耳蜗接种、人工耳蜗植入、人工耳蜗电刺激。在第4项研究中，我们将在接种耳蜗的耳内放置人工耳蜗，并评估有和没有恢复ihc的患者对电刺激和电诱发复合动作电位（ecap）的心理生理反应。一些毛细胞存活的对照组（即植入但未失聪的动物）将用于与毛细胞恢复的动物进行比较。我们提议的实验涉及使用我们实验室中已经存在的技术。这项工作得到了强有力的初步数据的支持，代表了相对低风险与非常高影响的理想结合。本实验将加深我们对哺乳动物耳蜗毛细胞再生的功能意义的理解，并有助于耳蜗植入与细胞替代治疗相结合的临床治疗感音神经性耳聋的发展。