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Effects of Localized Neurotrophin Gene Expression on Spiral Ganglion Neuron Resprouting in the Deafened Cochlea

机译:局部神经营养蛋白基因表达对耳聋耳蜗螺旋神经节神经元再生的影响

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摘要

A cochlear implant may be used to electrically stimulate spiral ganglion neurons (SGNs) in people with severe sensorineural hearing loss (SNHL). However, these neurons progressively degenerate after SNHL due to loss of neurotrophins normally supplied by sensory hair cells (HCs). Experimentally, exogenous neurotrophin administration prevents SGN degeneration but can also result in abnormal resprouting of their peripheral fibers. This study aimed to create a target-derived neurotrophin source to increase neuron survival and redirect fiber resprouting following SNHL. Adenoviral (Ad) vectors expressing green fluorescent protein (GFP) alone or in combination with brain-derived neurotrophic factor (BDNF) or neurotrophin-3 (NT3) were injected into the cochlear scala tympani or scala media of guinea-pigs (GPs) deafened via aminoglycosides for 1 week. After 3 weeks, cochleae were examined for gene expression, neuron survival, and the projection of peripheral fibers in response to gene expression. Injection of vectors into the scala media resulted in more localized gene expression than scala tympani injection with gene expression consistently observed within the partially degenerated organ of Corti. There was also greater neuron survival and evidence of localized fiber responses to neurotrophin-expressing cells within the organ of Corti from scala media injections (P < 0.05), a first step in promoting organized resprouting of auditory peripheral fibers via gene therapy.
机译:人工耳蜗可用于电刺激严重感觉神经性听力损失(SNHL)的人的螺旋神经节神经元(SGN)。然而,由于感觉毛细胞(HCs)通常提供的神经营养蛋白的丢失,这些神经元在SNHL后逐渐退化。实验上,外源性神经营养蛋白的给药可以预防SGN变性,但也可能导致其外周纤维异常重生。这项研究的目的是创建一个目标来源的神经营养蛋白源,以增加神经元的存活率,并在SNHL后重定向纤维再发芽。将表达绿色荧光蛋白(GFP)的单独或与脑源性神经营养因子(BDNF)或Neurotrophin-3(NT3)组合表达的腺病毒(Ad)载体注入耳聋的豚鼠耳蜗或Scala培养基中通过氨基糖苷治疗1周。 3周后,检查耳蜗的基因表达,神经元存活以及响应基因表达的外周纤维投射。将载体注射到scala培养基中比使用scala tympani注射产生更多的局部基因表达,并且在Corti的部分变性器官中始终观察到基因表达。皮下注射培养基后,Corti器官中神经元的存活率更高,并且对Corti器官中表达神经营养蛋白的细胞有局部纤维反应的证据(P <0.05),这是通过基因疗法促进听觉外周纤维组织再生的第一步。

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