GENETIC MODEL FOR CONGENITAL DEAFNESS

先天性、围产期或早发性听力损失大约发生在 美国每1000名新生儿中就有7名。尤其是年轻人， 噪声引起的听力损失越来越普遍。在成人 人口，超过50%的美国男性年龄>65岁有53分贝的损失， 4 kHz，严重损害正常语音的感知。主 这些听力受损组中每一组的病理组织学缺陷是 耳蜗底部附近的外（和内）毛细胞丢失，其中 高频声音被转换。 我们最近发现了一种突变的老鼠品种，叫做“摇摆鼠”。 (dfw)，其中听力在高频中受到最严重的影响 范围解剖学研究表明，外毛细胞（OHC）是缺席的， dfw耳蜗的基底区，在 低频率被听到的地方。内毛细胞（IHC）有时 在DFW耳蜗的基部缺失，但在中间和 顶区其他生理测量（例如耳蜗内 电位、第8神经传导和解剖结构似乎完好无损 在DFW。因此，dfw突变体提供了一个独特的遗传模型， 了解导致感音神经性耳聋的生理变化 以及耳蜗中功能性毛细胞的丧失。 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.）利用近交系分析法对东风汽车进行染色体定位 回交（IB）板在M. musculus（dfw）和M.栗色，刻痕 与分子微卫星标记相关的突变表型。这 小组将提供高分辨率的血统所需的成功 DFW的定位克隆。2.）的情况。克隆YAC中的dfw区域，建立 一个物理图谱和开发新的多态性标记， 在IB面板中更精确地定位DFW。3.）第三章屏幕 来自引起DFW的突变的区域的候选基因。4.）的情况。分析 dfw基因产物的结构和功能，5.） 进一步分析毛细胞损失的发育和空间变化， DFW模型。 这些研究将为研究人类免疫缺陷的分子基础提供新的视角。 先天性听觉毛细胞缺失，与毛细胞缺失直接相关 老化和噪音暴露。

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.