Proposed studies will examine archival and fresh human temporal bones as well as brains to examine and characterize age-related mitochondrial DNA mutations and correlate these with changes in proteins related to the mitochondrial function of oxidative phosphorylation as well as to histopathology. A hypothesis is, that there will be a relation between regions with the highest oxidative phosphorylation (e.g. spiral ganglion cells and stria vascularis) and age- related mitochondrial changes and cell loss. The characterization of mitochondrial DNA will involve DNA extraction and quantitative PCR. The experiments also involve cloning, amplification and analysis for point mutations and deletions in mitochondrial DNA. Oxidative phosphorylation will be assessed with immunocytochemistry for different cytochrome oxidase subunits and histochemical assessment of cytochrome oxidase and succinate dehydrogenase. Cochlear histopathology also will be assessed in the same region of each cochlea both in archival and fresh material. The first specific aim will be to compare changes in the cochlea with changes in specific brain regions with varying susceptibilities to acquired mitochondrial DNA damage. The second specific aim is to characterize changes in the cochlea of aged subjects with normal appearing cochlear histology. The third and final specific aim is to characterize changes in the cochlea of subjects whose cochlea show age-related histopathology.

Agency
National Institute of Health (NIH)
Institute
National Institute on Deafness and Other Communication Disorders (NIDCD)
Type
Research Project (R01)
Project #
1R01DC003395-01
Application #
2377604
Study Section
Special Emphasis Panel (ZDC1-SRB-J (14))
Project Start
1997-08-01
Project End
2000-07-31
Budget Start
1997-08-01
Budget End
1998-07-31
Support Year
1
Fiscal Year
1997
Total Cost
Indirect Cost
Name
University of California San Diego
Department
Surgery
Type
Schools of Medicine
DUNS #
077758407
City
La Jolla
State
CA
Country
United States
Zip Code
92093
Le, Tima; Keithley, Elizabeth M (2007) Effects of antioxidants on the aging inner ear. Hear Res 226:194-202
Keithley, Elizabeth M; Canto, Cecilia; Zheng, Qing Yin et al. (2005) Cu/Zn superoxide dismutase and age-related hearing loss. Hear Res 209:76-85
Keithley, Elizabeth M; Canto, Cecilia; Zheng, Qing Yin et al. (2004) Age-related hearing loss and the ahl locus in mice. Hear Res 188:21-8
Keithley, E M; Harris, B; Desai, K et al. (2001) Mitochondrial cytochrome oxidase immunolabeling in aged human temporal bones. Hear Res 157:93-9
Fischel-Ghodsian, N (2000) Homoplasmic mitochondrial DNA diseases as the paradigm to understand the tissue specificity and variable clinical severity of mitochondrial disorders. Mol Genet Metab 71:93-9
Keithley, E M; Truong, T; Chandronait, B et al. (2000) Immunohistochemistry and microwave decalcification of human temporal bones. Hear Res 148:192-6
Fischel-Ghodsian, N (1999) Mitochondrial deafness mutations reviewed. Hum Mutat 13:261-70
Keithley, E M; Erkman, L; Bennett, T et al. (1999) Effects of a hair cell transcription factor, Brn-3.1, gene deletion on homozygous and heterozygous mouse cochleas in adulthood and aging. Hear Res 134:71-6
Fischel-Ghodsian, N (1998) Mitochondrial genetics and hearing loss: the missing link between genotype and phenotype. Proc Soc Exp Biol Med 218:1-6
Fischel-Ghodsian, N (1998) Mitochondrial RNA processing and translation: link between mitochondrial mutations and hearing loss? Mol Genet Metab 65:97-104

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