Genetics of Age-related Hearing Loss

描述（由申请人提供）：老年性耳聋或年龄相关性听力损失（AHL）是老年人最常见的感觉缺陷，也是降低老年人生活质量的主要因素。人类的遗传研究很困难，因为发病较晚，而且非遗传因素，如噪音创伤、疾病和耳毒性药物会混淆解释。实验室小鼠为人类老年性痴呆提供了有希望的模型，因为AHL在近亲繁殖的小鼠品系中很常见，并且小鼠更易于进行详细的遗传和病理分析。小鼠和人类通常具有相同的基因和导致单基因听力障碍的内耳病理，因此对小鼠AHL的遗传研究可能会显著增加我们对人类老年性痴呆的理解。本提案的目的1是完成基因工程敲入小鼠的分析，以验证钙粘蛋白23基因（Cdh23）的剪接变体是ahl的基础，ahl是一种使ahl对多个近亲菌株易感性的变体，并从遗传学上分析菌株特异性对其表现的影响。Cdh23编码立体纤毛尖端连接的一个组成部分，这对毛细胞的机械转导至关重要，但目前尚不清楚Cdh23ahl变体如何影响AHL。我们之前的研究表明，毛细胞直立纤毛的肌动蛋白结合蛋白束蛋白2 （FSCN2）的错义突变是导致DBA/2J小鼠早发性听力损失的一个位点ah18的基础。ah18位于Chr 11远端。本提案的目的2是通过检测FSCN2敲除小鼠的毛束形态和听力损失进展，以及通过基因定位改变fscn2ah18对听力损失影响的菌株特异性位点，进一步阐明FSCN2在听觉功能中的作用。柠檬酸合酶（Cs）错配突变的染色体位置和菌株分布强烈支持它作为ah14相关的a /J小鼠听力损失的候选。目的3是通过BAC拯救方法确定AHL突变的致病性质，其中将野生型Cs转基因整合到a /J小鼠的基因组中。该目的的另一个方面是研究A/J ah14 （Cs）变异和先前描述的mt-Tr变异对耳蜗组织线粒体功能和氧化应激的影响。我们最近发现，具有γ -谷氨酰转移酶1（Ggt1）零突变（谷胱甘肽缺乏）的小鼠表现出进行性听力丧失，这与耳蜗内毛细胞的选择性丧失有关。目的4是详细检查内耳病变的进展，并测量与Ggt1突变小鼠听力损失相关的谷胱甘肽相关氧化应激参数。本研究的目的5是完善A/J小鼠（ahl9在Chr 11上）和NOD/ShiLtJ小鼠（ahl10在Chr 1上和ahl11在Chr 6上）的三个新定位位点的染色体位置并检测候选基因。

DESCRIPTION (provided by applicant): Presbycusis or age-related hearing loss (AHL) is the most common sensory deficit in aging human populations and a major factor in reducing the quality of life of the elderly. Genetic studies in humans are difficult because of the late onset of the condition and because non-genetic factors such as noise trauma, disease, and ototoxic drugs confound interpretations. The laboratory mouse provides promising models for human presbycusis because AHL is common in inbred mouse strains and mice are more amenable to detailed genetic and pathological analyses. Mice and humans often share the same genes and inner ear pathologies underlying monogenic hearing disorders, so genetic studies of AHL in mice are likely to add significantly to our understanding of human presbycusis. Aim 1 of this proposal is to complete the analysis of genetically engineered knock-in mice to verify that a splice variant of the cadherin 23 gene (Cdh23) underlies ahl, a variant conferring AHL susceptibility to multiple inbred strains, and to genetically analyze strain-specific influences on its manifestation. Cdh23 encodes a component of the stereocilia tip link, which is essential to hair cell mechanotransduction, but it is unclear how the Cdh23ahl variant influences AHL. We previously showed that a missense mutation of fascin 2 (FSCN2), an actin bundling protein of hair cell stereocilia, underlies ahl8, a locus on distal Chr 11 that contributes to the early onset hearing loss of DBA/2J mice. Aim 2 of this proposal is to further elucidate the role of FSCN2 in auditory function by examining hair bundle morphology and hearing loss progression in Fscn2 knockout mice, and by genetically mapping strain-specific loci that modify the effect of Fscn2ahl8 on hearing loss. The chromosomal location and strain distribution of a citrate synthase (Cs) missense mutation strongly supports it as a candidate for the ahl4-related hearing loss of A/J mice. Aim 3 is to determine the causative nature of this mutation on AHL by a BAC rescue approach, in which a wild-type Cs transgene is integrated into the genome of A/J mice. Another aspect of this aim is to investigate the effects of the A/J ahl4 (Cs) variant and a previously described mt-Tr variant on mitochondrial function and oxidative stress in cochlear tissues. We recently discovered that mice with a null mutation of gamma-glutamyltransferase 1(Ggt1), which are glutathione deficient, exhibit a progressive hearing loss that is associated with a selective loss of cochlear inner hair cells. Aim 4 is to examine in detail the progression of inner ear pathologies and to measure glutathione-related oxidative stress parameters related to the hearing loss of Ggt1 mutant mice. Aim 5 of this proposal is to refine the chromosomal locations and test candidate genes for three newly mapped loci that contribute to AHL in A/J mice (ahl9 on Chr 11) and NOD/ShiLtJ mice (ahl10 on Chr 1 and ahl11 on Chr 6).