Genetics of Age-Related Hearing Loss

项目摘要。老年性听力损失(老年性耳聋)的遗传基础尚不清楚。 因为研究这种迟发性复杂的遗传疾病是极其困难的。这个 实验室小鼠为研究人类老年性耳聋提供了有希望的模型，因为与年龄有关 听力损失(AHL)在近亲交配的小鼠品系中很常见，小鼠更容易接受遗传分析。 我们已经证明，10号染色体上的一个基因(AHL)是AHL的主要易感因素，在超过 10个近交系小鼠和另外三个基因(ah！2，ah！4和a/7/8)和一个线粒体突变 也会导致听力损失，特别是近交系。我们假设基因的易感性 而小鼠参与的病理生理途径也涉及到人类，而且进一步 小鼠急性耳聋的遗传学和病理学研究将大大加深我们对老年性耳聋的认识 在人类身上。我们的具体目标是：(1)正式检验CDH23变异与 AHL基因座致听力损失的基因敲入实验及分子分析 AHL发病机制及与其他基因的相互作用；(2)完善遗传图谱 定位并尝试确定负责a/7/2、ah！4和a/7/8的基因；以及(3)表征 与AHL基因座和近交系小鼠品系相关的内耳病理在AIMS 1和2中发展。 这项研究的长期目标是确定主要的遗传因素和分子 影响近交系AHL易感性、发病时间和病理表现的机制 作为人类老年性耳聋模型的小鼠品系。 与公共卫生的相关性。老年性耳聋是人类最常见的感觉缺陷； 大约三分之一的60岁以上的成年人患有严重的听力损失。拟议的遗传和 对小鼠年龄相关性听力损失的病理学研究将为改善我们的听力损失提供重要的启示 了解影响人类老年性耳聋的主要遗传因素和分子途径， 这可能有助于诊断、预防干预和治疗的发展。

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 three other genes (ah!2, ah!4, and a/7/8) 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 a/7/2, ah!4, and a/7/8; 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.