AIF基因敲除鼠的构建及在听神经病等耳聋疾病中的应用

发布时间：2018-03-10 16:13

本文选题：听神经病　切入点：凋亡诱导因子　出处：《第四军医大学》2016年博士论文　论文类型：学位论文

【摘要】：听神经病(auditory neuropathy,AN)是临床常见的一类特殊疾病,目前被称为听神经病谱系障碍(auditory neuropathy spectrum disorder,ANSD)因其临床症状特殊、发病机制不明及缺乏有效的治疗手段等一直是耳鼻咽喉头颈外科领域的研究热点。该病最主要的听力学改变包括听脑干反应(ABR)的缺失或严重波形异常,而耳蜗微音电位(CM)和耳声发射(DPOAE)正常,镫骨肌反射引不出或阈值升高,纯音听力检测多表现为低频听阈受损。病患的首要主诉是言语分辨率的下降,从而导致的交流障碍和随后带来的生活困扰。表现特殊的听神经病与常见的感音神经性聋之间的明显差别,引起了越来越多的耳鼻咽喉头颈领域的专家们的关注。但是,我们对于该病的病因、发病机制及病变的转归仍然不甚明朗。因此,探索和发现该病的发生、发展和转归,既有利于深入了解听神经病,也有利于我们指导患者的日常生活。近年来,我们课题组在迟发型听神经病家系中发现了数个新致聋基因,其中AIF表现为明确的X染色体隐性遗传的特点。该基因的致病特点与目前其他已知致病基因如OTOF、DIAPH3、PJVK等所引起的先天性听神经病表现明显不同,我们调查的这些家系中的患者均表现出青春期发病的特点,纯音听力检查一般表现为轻到中度感音神经性耳聋。我们课题组已成功制备了AIF条件性敲除模式动物,我们利用上述模式动物中的一种——螺旋神经元条件性AIF敲除动物为模型,初步研究了AIF这个新致聋基因所编码蛋白质的功能,初步判断AIF表达的缺失将导致耳蜗螺旋神经元的减少及模式动物听力学的改变。但其致聋机理及其它相关调控分子仍有待进一步研究。
[Abstract]:Auditory neuropathy (AND) is a kind of common clinical special disease. It is now called auditory neuropathy neuropathy spectrum disorder ANSDs because of its special clinical symptoms. Unknown pathogenesis and lack of effective treatment have been the focus of research in the field of otolaryngology and head and neck surgery. The main audiological changes of the disease include the absence of ABR (auditory brainstem response) or severe waveform abnormalities. Cochlear microphonological potential (CMV) and otoacoustic emission (OAE) were normal, stapedius reflex could not be induced or threshold increased, pure tone audiometry was mostly characterized by impaired low frequency hearing threshold. The primary complaint of patients was the decrease of speech resolution. The obvious difference between the presence of special auditory neuropathy and the common sensorineural hearing loss has attracted the attention of more and more experts in the field of otolaryngology, head and neck. We are still not clear about the etiology, pathogenesis and outcome of the disease. Therefore, to explore and discover the occurrence, development and outcome of the disease is conducive to a deeper understanding of auditory neuropathy. In recent years, our team has discovered several new deafening genes in families with delayed auditory neuropathy. Among them, AIF is the characteristic of X chromosome recessive inheritance. The pathogenicity of this gene is obviously different from that of congenital auditory neuropathy caused by other known pathogenetic genes, such as OTOF DIAPH3, PJVK and so on. The patients in the families we investigated all showed the characteristics of puberty, pure tone hearing test generally showed mild to moderate sensorineural hearing loss. Our team has successfully prepared AIF conditioned knockout model animal. We have studied the function of AIF, a novel deafness gene encoded by a novel deafness gene, using a conditioned AIF knockout model of helical neurons in the above model animals. It is preliminarily estimated that the absence of AIF expression will lead to the decrease of spiral neurons in cochlea and the change of auditory mechanics in model animals, but the mechanism of deafness and other related regulatory molecules need to be further studied.
【学位授予单位】：第四军医大学
【学位级别】：博士
【学位授予年份】：2016
【分类号】：R764.43

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