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Molecular mechanisms of endolymphatic hydrops and treatments for Meniere's disease

内淋巴积水的分子机制和梅尼埃病的治疗

基本信息

批准号：
15591813
负责人：
MISHIRO Yasuo
金额：
$ 2.24万
依托单位：
Osaka University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2003
资助国家：
日本
起止时间：
2003 至 2004
项目状态：
已结题

项目摘要

Steroid treatment for patients with inner ear disorders including Meniere's disease is usually performed, however the mechanism of steroid effects remains to be clarified. The aquaporins (AQPs) are a family of small transmembrane water transporters. It has been recently revealed that it makes a role in regulating homeostasis in the inner ear fluids. To elucidate action points of steroids in the inner ear, we first identified AQP1, 2, 3, 4, 5 and 6 mRNAs in the rat cochlea and AQP1, 3, 4, 5 and 6 in the rat endolymphatic sac by means of RT-PCR. Then, we found that intratympanic injections of steroids upregulated AQP1 mRNA of the rat cochlea in a dose-dependenct manner. These results suggest that steroids may be effective on the water homeostasis in the rat inner ear mainly via AQP1.The next aim of our study is to see if the endolymphatic sac is really available as a drug delivery system to make effects on the inner ear organs. We examined effects of a single insertion of dexamethasone into the rat unilateral endolymphatic sac on mRNA expression of the inner ear AQP family, transmembrane water transporters and putative endolymphatic fluid modulators, by means of real-time quantitative PCR. Only AQP-3 mRNA expression in the ipsilateral cochlea was significantly up-regulated in comparison with controls and the up-regulation was demonstrated both in dose-dependent and time-dependent manners. These findings suggest that the intra-endolymphatic sac steroids could make regulatory effects on the inner ear AQP-3 expression via vestibular aqueduct and modulate the homeostasis of endolymphatic fluids, encouraging the possibility that the endolymphatic sac could be a therapeutic window for the inner ear disease.

通常对患有内耳疾病（包括梅尼埃病）的患者进行类固醇治疗，但类固醇作用的机制仍有待澄清。水通道蛋白（aquaporins，AQP）是一类小型跨膜水转运蛋白。最近发现，它在调节内耳液中的稳态中起作用。为了阐明类固醇激素在内耳的作用点，我们首先用RT-PCR方法鉴定了大鼠耳蜗和内淋巴囊中AQP 1、2、3、4、5和6的mRNA。结果发现，鼓室内注射类固醇激素可上调大鼠耳蜗AQP 1 mRNA的表达，且呈剂量依赖性。这些结果表明，类固醇激素可能主要通过AQP 1对内耳水平衡起作用。我们下一步的研究目的是观察内淋巴囊是否真的可以作为药物传递系统对内耳器官起作用。我们通过实时定量PCR方法研究了地塞米松单次插入大鼠单侧内淋巴囊对内耳AQP家族、跨膜水转运蛋白和推定的内淋巴液调节剂mRNA表达的影响。与对照组相比，只有同侧耳蜗AQP-3 mRNA表达显著上调，且上调呈剂量依赖性和时间依赖性。提示内淋巴囊内类固醇激素可通过前庭导水管调节内耳AQP-3的表达，调节内淋巴液的稳态，内淋巴囊可能成为内耳疾病的治疗窗口。