Hearing loss in claudin 11-null mice

描述（由申请人提供）：该项目的长期目标是定义内耳血管纹紧密连接的功能，并确定由位于Scala介质周围的搏击连接组成的Claudin家族成员的多样性是否具有重叠或不重叠的性质。从这些研究中获得的知识将为血管纹在听力和钾循环到内淋巴中的作用提供深入的见解。具体目的是：1)验证Claudin//-缺失小鼠内耳病理源于形态缺陷的假设。Claudin 11在E13.5的胚胎和成人的前庭耳蜗发育中表达，并且在发育和出生后的总体结构变化的证据可以解释基因敲除小鼠的病理将被寻找。2)验证Claudin 11缺失小鼠出现早期听力缺陷的假设。年轻的成年敲除小鼠表现出听觉脑干反应（ABR）阈值升高，这表明听力损失，进一步测试ABR以及不同年龄的耳蜗电位和dpoae的测量将揭示这种表型是进行性的还是在小鼠正常开始听力时出现的。3)优化外源基因在血管纹基底细胞表达的转基因盒。已经掌握的基底细胞特异性增强元件将位于Claudin 11基因内，用于驱动耳蜗中β -半乳糖苷酶报告基因的表达，报告基因的表达将被描述为在耳蜗中表达几种Claudin cdna，试图挽救Claudin 11缺失小鼠的听力损失。

DESCRIPTION (provided by applicant): The long term goals of this project are to define the functions of tight junctions in Stria vascularis of the inner ear and to determine if the diversity of Claudin family members that comprise fight junctions located around Scala media have overlapping or non-overlapping properties. The knowledge gained from these studies will provide deep insights into the roles of the stria vascularis in hearing and potassium recycling to the endolymph. The specific aims are: 1) to test the hypothesis that inner ear pathology in Claudin//-null mice stems from morphological defects. Claudin 11 is expressed in the developing vestibulocochlear apparatus of embryos from E13.5 as well as in adults and evidence of gross structural changes during development and postnatally that could account for the pathology in the knockout mice will be sought. 2) to test the hypothesis that Claudin 11-null mice exhibit early hearing defects. Young adult knockout mice exhibit elevated auditory brainstem response (ABR) thresholds which indicate hearing loss, Further testing of ABRs as well as measurements of endocochlear potentials and DPOAEs at different ages will reveal if this phenotype is progressive or present at the time mice normally start to hear. 3) to optimize a transgene cassette for the expression of heterologous genes in basal cells of Stria vascularis. Basal cell-specific enhancer elements already in-hand will be located within the Claudin 11 gene and used to drive expression of a beta-galactosidase reporter gene in the cochlea, Reporter expression will be characterized with a view to expressing several claudin cDNAs in the cochlea in attempts to rescue hearing loss in Claudin 11-null mice.