Genetics of Age-Related Hearing Loss

描述（由申请人提供）：项目摘要。老年性听力损失的遗传基础知之甚少，因为研究这种迟发性遗传复杂疾病非常困难。实验室小鼠为研究人类老年性耳聋提供了有希望的模型，因为与年龄相关的听力损失（阿勒）在近交系小鼠中很常见，而且小鼠更适合遗传分析。我们已经证明，染色体10上的基因（阿勒）是超过10个近交系小鼠中阿勒的主要易感因素，另外3个基因（ahl 2，ahl 4和ahl 8）和线粒体突变也导致特定近交系小鼠的听力损失。我们假设，遗传易感性和病理生理学途径参与小鼠也参与人类和进一步的遗传和病理研究阿勒小鼠将显着增加我们的理解老年性耳聋在人类。我们的具体目标是：（1）通过基因“敲入”实验正式验证Cdh 23变异体与阿勒基因座所致听力损失有关的假设，并分析其影响阿勒的分子机制及其与其他基因的相互作用;（2）细化遗传图谱位置并尝试鉴定负责ahl 2、ahl 4和ahl 8的基因，以及（3）表征与阿勒基因座和在目的1和2中开发的近交系小鼠品系相关的内耳病理。本研究的长期目标是确定主要的遗传因素和分子机制，影响易感性，发病时间和病理表现的阿勒在近交系小鼠作为人类老年性耳聋的模型。与公共卫生的相关性。老年性耳聋是人类中最常见的感觉缺陷;大约三分之一的60岁以上的成年人患有严重的听力损失。拟议的小鼠年龄相关性听力损失的遗传和病理学研究将提供重要的见解，以提高我们对影响人类老年性耳聋的主要遗传因素和分子途径的理解，这可能有助于诊断，预防干预和治疗的发展。

DESCRIPTION (provided by applicant): Project Summary. The genetic basis of age-related hearing loss (presbycusis) is poorly understood because of the extreme difficulty in studying such a late-onset genetically complex disorder. The laboratory mouse provides promising models for studying human presbycusis because age-related hearing loss (AHL) is common in inbred mouse strains and mice are more amenable to genetic analyses. We have shown that a gene on Chromosome 10 (ahl) is a major susceptibility factor for AHL in more than 10 inbred strains of mice and that 3 other genes (ahl2, ahl4 and ahl8) and a mitochondrial mutation also contribute to hearing loss in particular inbred strains. We hypothesize that the genetic predisposition and the pathophysiological pathways involved in the mouse are also involved in humans and that further genetic and pathological studies of AHL in mice will add significantly to our understanding of presbycusis in humans. Our specific aims are to (1) formally test the hypothesis that a Cdh23 variant is responsible for the hearing loss attributed to the ahl locus by gene "knock-in" experiments and analyze the molecular mechanisms and interactions with other genes that underlie its effect on AHL; (2) refine the genetic map positions and attempt to identify the genes responsible for ahl2 ahl4 and ahl8 and (3) characterize the inner ear pathologies associated with the AHL loci and inbred mouse strains developed in Aims 1 and 2. The long-term objectives of this research are to identify the major genetic factors and molecular mechanisms that influence predisposition, time of onset, and pathological presentation of AHL in inbred strains of mice as models for human presbycusis. Relevance to public health. Presbycusis is the most common sensory deficit in human populations; about 1 in 3 adults older than 60 suffer from a significant hearing loss. The proposed genetic and pathological studies of age-related hearing loss in mice will provide important insights to improve our understanding of the major genetic factors and molecular pathways that influence human presbycusis, which could contribute to the development of diagnostics, preventive interventions, and therapies.