Mouse models to study inherited forms of deafness

描述（由申请人提供）：耳聋是一个主要的健康问题。每1000个儿童中就有1个天生耳聋，很大一部分老年人口受到与年龄有关的听力损失的折磨。许多形式的耳聋都是由基因引起的，但只有一部分与耳聋有关的基因被确定。迫切需要建立动物模型来研究听觉系统中的基因功能，确定听力损失的分子发病机制，并开发治疗耳聋的治疗方法。我的实验室的长期目标是阐明控制声音感知的分子机制，以及这个过程中导致耳聋的缺陷。作为实现这一目标的第一步，我们建议在小鼠中进行ENU突变筛选，以识别和研究控制听觉系统发育和功能的基因。我们假设我们将获得有价值的小鼠模型来分析控制听觉加工的机制和定义人类耳聋的分子发病机制。该假设基于以下数据：1)人类和小鼠的直系基因突变经常导致耳聋；ii)小鼠耳聋特征的ENU突变筛选为研究人类主要形式的耳聋提供了有用的动物模型；iii)我们进行了ENU突变筛选，以确定隐性和显性耳聋特征；我们已经鉴定出20种失聪的小鼠；iv)我们已经确定了钙粘蛋白23 （CDH23）基因的一个新的等位基因，这是已知的人类耳聋位点；v)对更多耳聋基因座的克隆已接近完成。我们已经确定的一些染色体区域以前与耳聋没有关联。我们预计将发现与耳聋有关的新基因。为了达到本提案的总体目标，我们与R. Smith博士（爱荷华大学）建立了合作关系，分析小鼠基因的人类同源基因突变在多大程度上导致耳聋。

DESCRIPTION (provided by applicant): Deafness is a major health problem. ~1 in 1000 children is born deaf and a large part of the aging population is afflicted by age-related hearing loss. Many forms of deafness are of genetic origin, but only a subset of the genes that are linked to deafness have been identified. There is also a pressing need for animal models to study gene function in the auditory system, to define the molecular pathogenesis of hearing loss, and to develop therapeutic approaches for treating deafness. The long-term goal of my laboratory is to elucidate the molecular mechanisms that control sound perception and the defects in this process that cause deafness. As a first step towards attaining this goal, we propose to carry out a ENU mutagenesis screen in mice to identify and study genes that control the development and function of the auditory system. We hypothesize that we will obtain valuable mouse models for analyzing the mechanisms that control auditory processing and for defining the molecular pathogenesis of deafness in humans. The hypothesis is based on the following data: i) mutations in orthologous genes frequently cause deafness in humans and mice; ii) ENU mutagenesis screens in mice for deafness traits have provided useful animal models for studying dominant forms of deafness in humans; iii) we have carried out an ENU mutagenesis screen to identify recessive and dominant deafness traits; we have identified 20 mouse strains that are deaf; iv) we have identified a novel allele of the cadherin 23 (CDH23) gene, a known deafness locus in humans; v) The cloning of additional deafness loci is nearing completion. Some of the chromosomal regions that we have identified have not been previously associated with deafness. We predict to identify novel genes that are associated with deafness.To reach the overall goal of this proposal, we have established a collaboration with Dr. R. Smith (University of Iowa) to analyze the extent to which mutations in human orthologs of the mouse genes cause deafness.