权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

The research for inner ear specific proteins and deafness gene coding proteins.

内耳特异性蛋白及耳聋基因编码蛋白的研究。

基本信息

批准号：
16591702
负责人：
TAKUMI Yutaka
金额：
$ 2.3万
依托单位：
Shinshu University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2004
资助国家：
日本
起止时间：
2004 至 2006
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-16591702/
关键词：
inner ear deafness gene COL9A3 CRYM thyroid hormone Na, K-ATPase β1 Ubiquitin A-52 K^+ recycling UbA52遺伝子難聴蝸牛血管条辺縁細胞前庭暗細胞 Na,K-ATPase 甲状腺ホルモン IX型コラーゲン蛋白ノックアウトマウス

项目摘要

Through cDNA microarray analysis of gene expression in the cochlea and vestibule, a number of genes that are highly expressed specifically in auditory tissues have been detected (Abe et al., 2003). Moreover, screening for genetic alterations in these genes has identified several possible disease-causing mutations. Here we targeted the COL9A3 (type IX collagen), mu-crystallin (CRYM) and ubiquitin A-52 residue ribosomal protein fusion product 1 (UbA52) genes that are highly expressed specifically in the cochlea and vestibule. The localization of the proteins coded by these genes and the mechanism of hearing disorders were examined in the inner ear.Immunocytochemical analysis revealed that type IX collagen is distributed in the tectorial membrane of the organ of Corti. To confirm the significance of type IX collagen for normal hearing, we assessed the detailed morphological and electrophysiological features of type IX collagen knock-out mice, which have recently been reported as a deafnes … More s model. Through assessment by auditory brainstem response (ABR), knock-out mice were shown to have progressive hearing loss.In a search for mutations of mu-crystallin (CRYM), a taxion specific crystalline which is also known as an NADP regulated thyroid hormone binding protein, two mutations were found at the C-terminus in patients with non-syndromic deafness. T3 binding activity of mutant mu-crystallin was compared with that of wild-type mu-crystallin, and one mutant was shown to have no binding capacity for T3, indicating that CRYM mutations cause auditory dysfunction through thyroid hormone binding properties. Immunocytochemical results indicated that mu-crystallin was co-localized with Na,K-ATPase within type II fibrocytes of the lateral wall. Therefore, CRYM mutations may cause auditory dysfunction through thyroid hormone binding effects on the fibrocytes of the cochlea. mu-Crystallin may be involved in the potassium ion recycling system together with Na,K-ATPase.The ubiquitin A-52 residue ribosomal protein fusion product 1 (UbA52) was found by immunocytochemical investigation to be distributed in the strial marginal cells and vestibular dark cells, which regulate the endolymphatic ion homeostasis. In the developing mouse cochlea, no significant staining was observed from birth to postnatal day 3, whereas after postnatal day 6, strong UbA52-immunoreactivities were observed in strial marginal cells. Endolymphatic K + concentration is elevated between postnatal days 3-8, therefore, our results indicate that UbA52 may have a functional role in regulation of ion secretion in the inner ear. Less

通过对耳蜗和前庭基因表达的cDNA微阵列分析，已经检测到许多在听觉组织中特异性高表达的基因（Abe et al., 2003）。此外，筛选这些基因的遗传改变已经确定了几种可能的致病突变。在这里，我们针对COL9A3 （IX型胶原），mu-crystallin （CRYM）和泛素A-52残基核糖体蛋白融合产物1 （UbA52）基因，这些基因在耳蜗和前庭中特异性高表达。这些基因编码的蛋白在内耳的定位和听力障碍的机制进行了研究。免疫细胞化学分析显示，IX型胶原蛋白分布在Corti器官的被膜中。为了证实IX型胶原蛋白对正常听力的意义，我们评估了IX型胶原蛋白敲除小鼠的详细形态学和电生理特征，该小鼠最近被报道为耳聋模型。通过听觉脑干反应（ABR）评估，敲除小鼠表现出进行性听力损失。在寻找微晶蛋白（CRYM）突变的过程中，在非综合征性耳聋患者的c端发现了两个突变。微晶蛋白是一种分类细胞特异性结晶，也被称为NADP调节的甲状腺激素结合蛋白。将突变体mu-crystallin与野生型mu-crystallin的T3结合活性进行比较，发现有一个突变体对T3没有结合能力，说明CRYM突变通过甲状腺激素的结合特性引起听觉功能障碍。免疫细胞化学结果显示，mu-crystallin与Na， k - atp酶在II型纤维细胞内共定位。因此，CRYM突变可能通过甲状腺激素对耳蜗纤维细胞的结合作用导致听觉功能障碍。mu-Crystallin可能与Na， k - atp酶一起参与钾离子循环系统。免疫细胞化学研究发现泛素A-52残基核糖体蛋白融合产物1 （UbA52）分布于庭侧边缘细胞和前庭暗细胞，调节内淋巴离子稳态。在发育中的小鼠耳蜗中，从出生到出生后第3天，没有观察到明显的染色，而出生后第6天，在耳蜗边缘细胞中观察到强烈的uba52免疫反应。在出生后3-8天内淋巴K +浓度升高，因此，我们的研究结果表明UbA52可能在调节内耳离子分泌中具有功能作用。少