Acquired hearing loss represents a complex interplay of genes and environment. Although there is much support for the existence of genes that influence the vulnerability of the cochlea to noise and ototoxins, few candidate genes or processes have been identified. One candidate process involves the generation and regulation of reactive oxygen species (ROS). Both chronic neurodegenerative disease and acute CNS injury involve elevated ROS, and deficiency of antioxidant enzymes promotes vulnerability to injury. We hypothesize that some genetic defects that predispose people to acquired hearing loss involve impairment of ROS regulatory mechanisms, rendering the cochlea more vulnerable to injury. We will apply hearing loss-prone and -resistant mouse models (C57BL/6, BALB/c, CBA/Ca), and 'knockout' mice deficient in antioxidant enzymes (superoxide dismutase and glutathione peroxidase), of carefully considered ages to the following Specific Aims: (1) Correlating the dynamics of cochlear ROS production following noise exposure with specific cochlear injury. We will establish the relation between the magnitude and time course of cochlear ROS production following acute noise exposure and cochlear injury, as measured by auditory brainstem responses, light and electron microscopy, and hair cell counts. (2) Identifying genetic influences on the relation between ROS production and noise-induced cochlear injury. We will determine the impact of genetic defects of hearing and ROS regulation on the relation between cochlear ROS production and noise-induced cochlear injury. (3) Uncovering the basis of genetic and age influences on the efficacy of antioxidants. We will determine the impact of age and genetic defects of hearing on the ability of exogenous antioxidants to attenuate both ROS production and noise-induced cochlear injury. Our experiments will establish how well the dynamics of ROS production predict cochlear injury, and whether progressive deafness genes may impair cochlear ROS regulation.

Agency
National Institute of Health (NIH)
Institute
National Institute on Deafness and Other Communication Disorders (NIDCD)
Type
Research Project (R01)
Project #
5R01DC003454-02
Application #
6176818
Study Section
Special Emphasis Panel (ZRG1-IFCN-6 (01))
Program Officer
Freeman, Nancy
Project Start
1999-08-01
Project End
2004-07-31
Budget Start
2000-08-01
Budget End
2001-07-31
Support Year
2
Fiscal Year
2000
Total Cost
$198,583
Indirect Cost
Name
Central Institute for the Deaf
Department
Type
DUNS #
City
Saint Louis
State
MO
Country
United States
Zip Code
63110
Ohlemiller, Kevin K; Rybak Rice, Mary E; Rosen, Allyson D et al. (2011) Protection by low-dose kanamycin against noise-induced hearing loss in mice: dependence on dosing regimen and genetic background. Hear Res 280:141-7
Ohlemiller, Kevin K; Rybak Rice, Mary E; Rellinger, Erin A et al. (2011) Divergence of noise vulnerability in cochleae of young CBA/J and CBA/CaJ mice. Hear Res 272:13-20
Ohlemiller, Kevin K; Rosen, Allyson D; Rellinger, Erin A et al. (2011) Different cellular and genetic basis of noise-related endocochlear potential reduction in CBA/J and BALB/cJ mice. J Assoc Res Otolaryngol 12:45-58
Ohlemiller, Kevin K; Dahl, Ashley R; Gagnon, Patricia M (2010) Divergent aging characteristics in CBA/J and CBA/CaJ mouse cochleae. J Assoc Res Otolaryngol 11:605-23
Fernandez, Elizabeth A; Ohlemiller, Kevin K; Gagnon, Patricia M et al. (2010) Protection against noise-induced hearing loss in young CBA/J mice by low-dose kanamycin. J Assoc Res Otolaryngol 11:235-44
Ohlemiller, Kevin K; Rosen, Allyson D; Gagnon, Patricia M (2010) A major effect QTL on chromosome 18 for noise injury to the mouse cochlear lateral wall. Hear Res 260:47-53
Ohlemiller, Kevin K; Rice, Mary E Rybak; Lett, Jaclynn M et al. (2009) Absence of strial melanin coincides with age-associated marginal cell loss and endocochlear potential decline. Hear Res 249:1-14
Ohlemiller, Kevin K (2009) Mechanisms and genes in human strial presbycusis from animal models. Brain Res 1277:70-83
Ohlemiller, Kevin K; Rice, Mary E Rybak; Gagnon, Patricia M (2008) Strial microvascular pathology and age-associated endocochlear potential decline in NOD congenic mice. Hear Res 244:85-97
Ohlemiller, Kevin K (2008) Recent findings and emerging questions in cochlear noise injury. Hear Res 245:5-17

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