Identification of ARHL Genes and their Molecular and Functional Modifiers

项目摘要/摘要 Claudin家族由跨膜蛋白组成，跨膜蛋白是紧密连接的重要组成部分。 在上皮组织和内皮组织中形成屏障。在耳蜗组织中，Claudin 9(Cldn9)在 高钾(K+)内淋巴与低钾(K+)内淋巴分离的Corti器官紧密连接 外淋巴液对于保护外毛细胞以及维持外淋巴液是必要的。 耳蜗内电位(EP)(Nakano等人，2009，Wangemann和Schacht，1996)。 我们的实验室专注于识别抵抗噪音应激的基因(Street等人)。2014年)。在五个人中 在129S6/SvEvTac(129S6)品系中出现的数量性状基因座(QTL)，最强的QTL包含 Cldn9.令人惊讶的是，当我们开始研究噪声敏感性时，很明显这个轨迹也 表现为年龄相关性听力损失(AHL)表型为非进行性听力损失(NPHL)， 显著的中频性急性淋巴细胞性白血病12个月。 为了探索Cldn9的功能属性，我们最近开发了一个由强力胞苷(Dox)调控的版本 可以上调或下调的Cldn9基因。我们确信，我们在DOX后观察到的变化 操作是由Cldn9表达式引起的。在这里，我们将研究Cldn9在听力老化中的作用。 系统，包括影响噪声和Cldn9‘S在钾素渗漏中的作用问题。

PROJECT SUMMARY/ABSTRACT The claudin family is composed of transmembrane proteins that are an essential part of the tight junctions forming barriers in epithelial and endothelial tissue. In the cochlea, Claudin 9 (Cldn9) is highly expressed in the tight junctions of the organ of Corti, where separation of high potassium (K+) endolymph from the low K+ perilymph fluid is necessary for protection of the outer hair cells (OHCs), as well as for maintaining the Endocochlear Potential (EP) (Nakano et al 2009, Wangemann and Schacht, 1996). Our lab has focused on identifying genes that are resistant to noise stress (Street, et al. 2014). Among the five quantitative trait loci (QTL) that appeared in the 129S6/SvEvTac (129S6) strain, the strongest QTL contains Cldn9. Surprisingly, when we started to study the noise sensitivity it became apparent that this locus also displayed an age-related hearing loss (AHL) phenotype that was non-progressive hearing loss (NPHL), and a significant mid-frequency ARHL by 12 months. To explore functional attributes of Cldn9, we have recently developed a Doxycyline (dox) regulated version of the Cldn9 gene that can be up or down regulated. We are assured that the changes that we observe after dox manipulation are due to the Cldn9 expression. Here we will examine the role of Cldn9 in an aging auditory system, including the influence noise and the question of Cldn9’s role in potassium leakage.