Acoustic and electrical hearing after Atoh1 treatment

Atoh1 治疗后的声学和电学听力

基本信息

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
项目类别：
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

项目摘要

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.

我们最近证明了哺乳动物中生成新的内毛细胞（IHC）基因疗法后的皮质器官。具体而言，实验涉及体内接种腺病毒载体与Atohl基因插入物（m.atohl）进入成熟的豚鼠耳蜗中。我们还证明了新的毛细胞可以吸引神经元。用的耳朵治疗 Atohl表现出部分恢复功能的部分恢复，如Preyer的反射和声学诱发听觉脑干响应（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措施，以定义恢复的性质和程度声学听证会。我们还将进行与这种AtoHl治疗有关的实验与人工耳蜗的结合。对于前两个具体目的，我们将用耳毒性药物对豚鼠倾斜并测量心理物理检测（目标1）和歧视（目标2）以及ABR和失真产物耳声排放（DPOAE）。在AIM 3中，我们将评估m.atohl之间的相互作用接种，人工耳蜗植入和对耳蜗的电刺激。在目标4中，我们将将人工耳蜗植入物放在接种的耳朵中，并评估对电气的心理物理反应具有和不恢复IHC的刺激和电诱发的复合作用电位（ECAP）。具有某些存活的毛细胞的对照（即，将使用植入但不植入的动物）与恢复毛细胞的动物进行比较。我们提出的实验涉及我们已经存在的技术实验室。这项工作得到了强大的初步数据的支持，代表了理想的组合相对较低的风险，影响很高。提出的实验将增强我们对哺乳动物耳蜗中毛细胞再生的功能意义，并有助于开发涉及人工耳蜗的临床疗法用于感觉性耳聋植入细胞替代疗法。