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名儿童中就有1人天生耳聋，大部分老龄化人口患有与年龄相关的听力损失。许多形式的听力损失都是遗传性的，但与这种疾病有关的大多数基因仍然需要鉴定。研究听觉系统基因功能的动物模型和开发治疗听力损失的治疗方法也是迫切需要的。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导致听力损失的这一过程中的缺陷。作为实现这一目标的一步，我们在这里建议扩展我们在小鼠中的前向遗传筛选，该筛选是在前一个资助期启动的，目的是产生患有先天性耳聋的小鼠品系。同时，我们优化了我们的筛选，并假设它将为研究人类先天性、进行性和迟发性听力损失的分子发病机制提供有价值的动物模型。这一假设是基于我们已发表的初步数据，这些数据表明，我们已经在筛选中产生了患有各种形式的听力损失的小鼠品系，这些听力损失是由与人类疾病相关的基因突变引起的。为了实现我们的总体目标，我们将通过ENU诱变产生额外的听力障碍小鼠品系，定位克隆受影响的基因，表征小鼠表型，并寻找与我们在筛选中鉴定的小鼠基因正交的人基因中的突变。由于超过60%的与听力损失相关的基因仍需要鉴定，我们预计我们将鉴定出与人类听力损失相关的其他基因，并为人类疾病建立小鼠模型。我们的小鼠品系对于测试治疗听力损失的治疗方法将是有价值的。

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 hearing loss are of genetic origin, but the majority of genes that are linked to the disease still need to be identified. There is also a pressing need for animal models to study gene function in the auditory system and to develop therapeutic approaches for treating hearing loss. 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 hearing loss. As a step towards attaining this goal, we propose here to extend our forward genetic screen in mice that was initiated in the previous funding period with the aim to generate mouse lines afflicted with congenital deafness. We have in the meantime optimized our screen and hypothesize that it will provide valuable animal models for studying the molecular pathogenesis of congenital, progressive, and late-onset forms of hearing loss in humans. This hypothesis is based on our published and preliminary data, which show that we have already generated in our screen mouse lines afflicted with various forms of hearing loss caused by mutations in genes linked to the human disease. To achieve our overall goal, we will generate by ENU mutagenesis additional mouse lines with hearing impairment, positionally clone the affected genes, characterize the mice phenotypically and search for mutation in human genes orthologous to the mouse genes that we identify in our screen. As more than 60% of the genes that are linked to hearing loss still need to be identified, we anticipate that we will identify additional genes that are linked to hearing loss in humans and generate mouse models for the human disease. Our mouse lines will be valuable for testing therapeutic approaches towards treating hearing loss.