GENETIC MODEL FOR CONGENITAL DEAFNESS

先天性、围产期或早发性听力损失大约发生在 在美国，每1000名新生儿中就有7名。尤其是在年轻人中， 噪声性听力损失越来越常见。在成人中 人口，超过50%的65岁美国男性在 4 kHz，严重损害正常语音的感知。初级阶段 这些听力受损人群的病理组织学缺陷是 耳蜗基底部附近的外毛细胞(和内毛细胞)丢失， 高频声音被转换。 我们最近发现了一种突变的小鼠品系，名为deafwaddler (DFW)，在高频下听力受到的影响最严重 射程。解剖学研究表明，外毛细胞(OHC)在 DFW的耳蜗基底区，在耳蜗区附近变得更频繁 可以听到低频的顶点。内毛细胞有时 在DFW耳蜗底缺失，但在中部和中部显示完好无损 顶端区域。其他生理指标(例如内耳 电位、第八神经传导和解剖结构似乎完好无损。 在DFW。因此，Dfw突变体提供了一种独特的遗传模式 了解导致感音神经性耳聋的生理变化 以及耳蜗区功能毛细胞的丧失。 在这里，我们建议通过定位克隆技术来鉴定DFW基因。 我们将：1.)通过自交系分析确定东方红S的染色体定位 肌肉分枝杆菌(DFW)与卡氏分枝杆菌的回交(IB)板，得分 相对于分子微卫星标记的突变表型。这 Panel将提供成功所需的高分辨率谱系 DFW的定位克隆。2.)克隆YAC中的DFW区域，建立 物理地图和开发新的多态标记将被评分 在IB面板中，以便更准确地定位DFW。3.)屏幕 导致DFW的突变区域的候选基因。4.)分析 DFW基因产物的结构和功能与5.) 进一步分析毛细胞缺失的发育和空间变化。 DFW模型。 这些研究应该会为人类免疫缺陷的分子基础提供新的见解 先天性听性毛细胞缺失，并与毛细胞缺失直接相关 在老化和由于噪音暴露。

Congenital, perinatal, or early onset hearing loss occurs in approximately 7 out of 1000 neonates in the United States. Especially in young people, noise-induced hearing loss is increasingly common. In the adult population, more than 50% of U.S. males age >65 years have a 53dB loss at 4 kHz, substantially impairing perception of normal speech. The primary pathohistological defect in each of these hearing impaired groups is the loss of outer (and inner) hair cells near the base of the cochlea, where high frequency sounds are transduced. We have recently identified a mutant mouse strain, called deafwaddler (dfw), in which hearing is most severely affected in the high frequency range. Anatomical studies show that outer hair cells (OHC) are absent from the basal region of the cochlea in dfw, becoming more frequent near the apex where low frequencies are heard. Inner hair cells (IHC) are sometimes missing at the base of dfw cochlea but appear intact in the mid- and apical regions. Other physiological measures (e.g. endocochlear potentials, 8th nerve conduction, and anatomical structures appear intact in dfw. Thus, the dfw mutant provides a unique genetic model for understanding the physiological changes leading to sensorineural deafness and loss of functional hair cells in the cochlea. Here we propose to identify the dfw gene by positional cloning techniques. We will: 1.) Refine dfw 's chromosomal location by analyzing inbred backcross (IB) panels between M. musculus (dfw) and M. castaneus, scoring the mutant phenotype relative to molecular microsatellite markers. This panel will provide the high resolution pedigree required for successful positional cloning of dfw. 2.) Clone the dfw region in YACs, establishing a physical map and developing new polymorphic markers that will be scored in IB panel for yet more accurate localization of dfw. 3.) Screen candidate genes from the region for the mutation causing dfw. 4.) Analyze the structure and function of the dfw gene product in parallel with, 5.) Further analyze the developmental and spatial changes in hair cell loss in the dfw model. These studies should provide new insight into the molecular basis of congenital auditory hair cell loss, and relate directly to hair cell loss in aging and due to noise exposure.