Genetics of Age-Related Hearing Loss

描述(申请人提供)：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，因为研究这种晚发的复杂的遗传疾病是极其困难的。实验室小鼠为研究人类老年性耳聋提供了有希望的模型，因为年龄相关性听力损失(AHL)在近亲交配的小鼠品系中很常见，而且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10多个近交系小鼠AHL的主要易感因素，另外3个基因(ah12、ah14和ah18)和线粒体突变也与听力损失有关，特别是近交系。我们假设，小鼠的遗传易感性和涉及的病理生理途径也涉及到人类，进一步的小鼠AHL的遗传和病理学研究将大大增加我们对人类老年性耳聋的理解。我们的具体目标是：(1)通过基因敲入实验正式检验CDH23突变导致AHL基因座听力损失的假设，并分析其影响AHL的分子机制及其与其他基因的相互作用；(3)研究与AHL基因座和近交系小鼠AHL相关的内耳病理学特征。本研究的长期目标是确定影响近交系小鼠AHL的易感性、发病时间和病理表现的主要遗传因素和分子机制，作为人类老年性耳聋的模型。与公共卫生的相关性。老年性耳聋是人类最常见的感觉障碍；60岁以上的成年人中约有1/3患有严重的听力损失。对老年性耳聋小鼠的遗传学和病理学研究将为我们更好地理解影响人类老年性耳聋的主要遗传因素和分子途径提供重要的见解，这将有助于诊断、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.