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

Transducin(b)like 1 (TBL1) 在退行性听力损失中的作用

• 批准号: 7003660
• 负责人: Emmanuele Delot
• 金额: $ 29.87万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-01-01 至 2007-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7003660
• 关键词: alleles; biological models; cell type; disease /disorder onset; gene interaction; gene targeting; genetic regulation; genetic transcription; genetically modified animals; histology; immunoprecipitation; laboratory mouse; labyrinth; mutant; protein binding; protein structure function; sensorineural hearing loss; tissue /cell culture; transducin

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.

描述（由申请人提供）：听力损失是人类最常见的感觉缺陷。它影响1/1000的新生儿和10%的总人口。听力问题的人数随着年龄的增长而稳步增加，在90岁以上的人中，听力问题的人数高达50%。因此，在人口日益老龄化的时代，这是一个重大的公共卫生问题。只有在过去的几年里，研究才开始揭示成年期发病的进行性听力损失的病因学相关的基因。然而，尽管与迟发性听力障碍相关的基因座数量稳步增加，但由于缺乏合适的动物模型，导致疾病的基因的最终鉴定经常受到阻碍。此外，很少有基因可能诱发听力缺陷和/或使自己的治疗方法已被确定。 在这里，我们建议执行一个整体的机制，导致退行性听力损失的遗传，分子和功能技术的研究转导蛋白（β）像1（TBL 1）和TBL 1相关蛋白（TBLR 1）基因。TBL 1最近在人类中与迟发性感音神经性耳聋的出现相关。TBLR 1是TBL 1的同源物，当TBL 1在培养物中失活时提供功能补偿，因此，很可能tblr 1的冗余活性可以掩盖小鼠中tbll失活的表型效应。我们已经克隆了小鼠tbll和tblrl，并制备了这两个基因的靶向构建体。我们打算使用靶向结构来产生每一个基因的突变小鼠。我们将使用这些动物模型来研究tbll和tblrl在调节对内耳稳态至关重要的基本遗传途径中的作用。为了实现这一目标，我们的具体目标将是：（1）通过产生携带tb 111基因突变等位基因的小鼠，以确定tb 111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tbllrl基因突变等位基因的小鼠来确定tbllrl在迟发性感音神经性聋发病机制中的作用。(3)表征tbll突变等位基因的结合和阻遏物特性。 这些实验的长期目标是了解人类迟发性退行性听力损失开始和进展的遗传机制。