Otitis media (OM), one of the most common human diseases, is affected by multiple factors including Eustachian tube (ET), immune status, innate mucosal defense, pathogens, and genetic susceptibility. The mouse is the premier animal model for human disease research, and mouse models of OM represent powerful tools for advancing the understanding of OM. The broad, long-term objectives of this research are: to identify novel genes and/or novel functions of known genes that underlie OM susceptibility using a functional genomic and phenotyping driven approach and to develop innovative treatment strategies for human OM using genetic mouse models. The immediate goals are to identify, develop, and characterize genetic mouse models for OM by utilizing the unique mouse genetic and mutant resources at The Jackson Laboratory (TJL). TJL maintains more than 2,500 strains of mice, including inbred mice, mice with spontaneous mutations, and genetically engineered mice. Moreover, two large-scale mutagenesis programs at TJL are generating more than 1,000 mutagenized mice every month. Collectively, these valuable genetic resources offer an exceptional opportunity for the identification of new mouse models of OM. To provide the hearing research community with new models for the study of OM, we will:
Aim 1. Develop techniques for diagnosis of OM in the mouse. We will focus on the adaptation of clinical tympanometry (tymp) and video-otoscopy (v-oto) techniques for the analysis of mice. We will test the sensitivity and specificity of these two tools in the mice by matched pathological studies of several potential or known genetic mouse models of OM.
Aim 2. Test the hypothesis that heritable host traits influence OM development by identifying and characterizing genetic mouse models of OM. We will perform a two-level screening of mice at TJL for OM susceptibilities and then carry out heritability testing to identify genetic mouse models. The screening strategy comprises a primary screen for elevated auditory brainstem response (ABR) thresholds and vestibular deficits (head tilting and circling), followed by a secondary screen of identified mice using our techniques developed in Aim 1 for the characterization of middle ear (ME) structure and function.
Aim 3. Develop a pathogen-challenge methodology to evaluate genetic mouse models of OM identified in aim 2 by comparing their pathogen-challenge responses with those of controls.
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