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.
