Mouse models to study inherited forms of deafness

描述(申请人提供)：耳聋是一个主要的健康问题。大约每1000名儿童中就有1名出生时耳聋，很大一部分老龄化人口受到年龄相关性听力损失的困扰。许多形式的听力损失都是由基因引起的，但与这种疾病有关的大多数基因仍然需要识别。还迫切需要动物模型来研究听觉系统中的基因功能，并开发治疗听力损失的治疗方法。我的实验室的长期目标是阐明控制声音感知的分子机制，以及这一过程中导致听力损失的缺陷。作为实现这一目标的一步，我们在这里建议扩大我们在前一个资助期启动的小鼠的正向基因筛查，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和假设，它将为研究人类先天性、进行性和晚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公布的初步数据，这些数据表明，我们已经在屏幕上产生了因与人类疾病相关的基因突变而导致的各种形式听力损失的小鼠品系。为了实现我们的总体目标，我们将通过ENU突变产生额外的听力障碍小鼠品系，定位克隆受影响的基因，对小鼠的表型进行鉴定，并在与我们在屏幕上识别的小鼠基因同源的人类基因中寻找突变。由于60%以上与听力损失有关的基因仍需识别，我们预计我们将识别更多与人类听力损失有关的基因，并建立人类疾病的小鼠模型。我们的小鼠品系将对测试治疗听力损失的治疗方法有价值。 公共卫生相关性：听力损失是一个主要的健康问题，通常是由基因引起的，但与这种疾病有关的大多数基因尚不清楚。我们建议通过突变产生具有听觉功能缺陷的小鼠模型，以确定导致耳聋的基因突变。我们将确定与老鼠基因同源的人类基因突变对听力的影响程度，并研究疾病机制。

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. PUBLIC HEALTH RELEVANCE: Hearing loss is a major health problem and frequently of genetic origin, but the majority of genes that are linked to the disease is not known. We propose here to generate by mutagenesis mouse models with defects in auditory function to identify gene mutations that cause deafness. We will determine the extent to which mutations in human genes orthologous to the mouse genes affect hearing and study disease mechanisms.