Genetics of Noise Resistance in the Aging Ear

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DESCRIPTION (provided by applicant): Hearing losses that accumulate with chronic exposure to high-level sound (noise-induced hearing loss; NIHL) and with age (age-related hearing loss; AHL or presbycusis) are major health problems. They are common, their consequences are permanent, and their impact on human communication and quality of life is significant. Important advances have been made in characterizing the structural changes in the ear that underlie both NIHL and AHL, however, the mechanisms underlying these changes are still poorly understood. In human populations, hearing losses secondary to noise exposure and those attributed to aging are highly variable between individuals: some have 'tough' ears, while others have 'tender' ears. In contrast, work with laboratory mice has shown significantly less variability in NIHL and/or AHL within one inbred strain, while there are striking differences between strains. Our long-term goal is to exploit these strain differences in mouse models to study the genetic factors influencing susceptibility to NIHL and AHL, and interactions between them. Our immediate goals focus on the remarkable resistance to NIHL in the inbred mouse strain l29S6/SvEvTac (129S6), recently reported by the Liberman laboratory. Whereas NIHL typically grows rapidly once a critical exposure level is reached, NIHL in 129S6 grows 10 times more slowly over a wide range of exposure energy. Preliminary results from the Kujawa laboratory suggest that 129S6 also shows a type of AHL, demonstrating that AHL vulnerability need not be linked to NIHL vulnerability, as they appear to be in C57BL/6 mice. Further preliminary results from a Kujawa/Tempel collaboration suggest that both the AHL and the NIHL resistance in 129S6 are heritable as recessive traits. With this foundation, we propose to 1) better characterize the AHL and the influence of AHL on NIHL resistance in 129S6 using a number of physiological and histopathological measures, 2) provide a chromosomal localization for the major gene(s) influencing noise resistance in 129S6 using well-established techniques for genetic mapping, and 3) using the same genetic techniques, establish whether the AHL in 129S6 is mediated by the same gene locus associated with AHL in the C57BL/6 strain. The ultimate characterization of the genes influencing susceptibility to AHL and NIHL will provide fundamental insight into the cellular and molecular processes underlying cochlear degeneration, which, in turn, will be key to devising effective strategies to preserve hearing in human populations.