Transducin(b)like 1 (TBL1) in degenerative hearing loss

描述(申请人提供)：听力损失是人类最常见的感官缺陷。每1000名新生儿中就有1人受到影响，占总人口的10%。听力问题的人数随着年龄的增长而稳步增加，在达到第九个十年的人中，听力问题的人数上升了50%。因此，在人口日益老龄化的时代，这是一个主要的公共卫生问题。直到最近几年，研究才开始发现与成年期发病的进行性听力损失的病因学有关的基因。然而，尽管与迟发性听力障碍有关的基因座数量稳步增加，但导致这些疾病的基因的最终鉴定往往因缺乏合适的动物模型而受阻。此外，很少有可能导致听力缺陷和/或有助于治疗方法的基因被识别出来。 在这里，我们建议通过应用遗传、分子和功能技术来研究转导蛋白(β)样蛋白1(TBL1)和TBL1相关蛋白(TBLR1)基因，对导致退行性听力损失的机制进行综合分析。最近在人类中，TBL1与迟发性感音神经性耳聋的出现有关。Tblr1是TbL1的同系物，当TbL1在培养中失活时，它提供功能补偿，因此，Tblr1的多余活性很可能掩盖了Tbll失活的表型效应。我们已经克隆了小鼠tbll和tblrl，并为这两个基因准备了靶向构建体。我们打算使用靶向构建体来为每个基因产生突变小鼠。我们将使用这些动物模型来研究Tbll和Tblrl在调节对内耳内环境稳定至关重要的基本遗传途径中的作用。为了实现这一目标，我们的具体目标是：(1)通过产生携带tb111基因突变等位基因的小鼠，确定tb111在迟发性感音神经性耳聋发病机制中的作用。(2)通过产生携带Tbllr1基因突变等位基因的小鼠，确定Tbllrl在迟发性感音神经性耳聋发病机制中的作用。(3)研究Tbl1突变等位基因的结合和抑制特性。 这些实验的长期目标是了解人类迟发性退行性听力损失的开始和进展所涉及的遗传机制。

DESCRIPTION (provided by applicant): Hearing loss is the most common sensory deficit in humans. It affects 1 in 1000 newborns and 10% of the general population. The number of people with hearing problems increases steadily with age, rising up to 50% of those reaching the 9th decade of life. It is therefore a major public health concern in times of an increasingly older population. Only in the last few years have researches started to uncover the genes involved in the etiology of progressive hearing loss with onset during adulthood. However, although the number of loci linked to late-onset hearing deficits increases steadily, the final identification of the genes responsible for the disorders is frequently hampered by the lack of suitable animal models. Moreover, very few genes that may be predisposing for hearing defects and/or that lend themselves to therapeutic approaches have been identified. Here we propose to perform an integral analysis of the mechanisms leading to degenerative hearing loss by applying genetic, molecular and functional techniques to the study of the Transducin (beta) like1 (TBL1) and TBLl-related protein (TBLR1) genes. TBL1 has been recently associated in humans with the appearance of late-onset sensorineural deafness. TBLR1 is a homologue of TBL1 that provides functional compensation when TBL 1 is inactivated in culture, it is therefore, very likely that the redundant activity of tblrl could mask the phenotypic effects of tbll inactivation in mice. We have cloned mouse tbll and tblrl and prepared targeting constructs for both genes. We intend touse the targeting constructs to generate mutant mice for each one of the genes. We will use these animal models to investigate the role of tbll and tblrl in the regulation of basic genetic pathways that are critical for the homeostasis of the inner ear. In order to achieve this objective our specific aims will be: (1) To determine the role of tb111 in the pathogenesis of late-onset sensorineural deafness by generating mice carrying a mutant allele of the gene. (2) To determine the role of tbllrl in the pathogenesis of late-onset sensorineural deafness by generating mice carrying a mutant allele of the gene. (3) To characterize the binding and repressor properties of tbll mutant alleles. The long-term goal of these experiments is to understand the genetic mechanisms involved in the commencement and progression of late-onset degenerative hearing loss in humans.