The mammalian auditory system-- unrivaled in sensitivity and frequency discrimination -- is susceptible to a host of afflictions that compromise acoustic performance. The key to the prevention or cure of hearing disorders resides in a thorough knowledge of auditory transduction and transmission. Despite rapid advances in our understanding of the mechanico-electrical aspects of auditory function, our appreciation of the underlying macromolecular mechanisms remains fragmentary. Although the cells of the mammalian auditory organ, the organ of Corti (OC), express thousands of proteins, a small minority are directly associated with the transduction/transmission processes. Detailed characterization of these molecular auditory components will furnish substantial insight into auditory function. OCP1 and OCP2 -- expressed specifically and abundantly in the OC -- are members of this elite subset. On the microscale, OCP2 is expressed in a pattern that exactly mirrors the epithelial gap junction system of the cochlea. Whether this intriguing anatomical association has functional significance, or whether it is merely coincidental, is uncertain. The available evidence suggests that OCP1 and OCP2 are subunits of vital multi-protein regulatory complexes, conceivably the same complex. The identification of additional subunits is the immediate project objective. The OCPs -- i.e., OCP1, OCP2, and their associated polypeptides -- will then be subjected to a battery of biochemical, molecular biological, physical, and morphological techniques. Sequence information, derived from the cloned cDNAs, will reveal potential sites for post-translational modification and potential ligand-binding motifs. Functionality of these structural features will be assessed biochemically. Recombinant OCPs will be investigated by analytical ultracentrifugation, optical spectroscopy (fluorescence and circular dichroism), microcalorimetry, and NMR spectroscopy. Expression of the OCPs at the mRNA and protein levels will be examined as a function of age and development in the guinea pig, rat, and gerbil, and in OC- derived cell lines. Alterations in expression will also be monitored in OC-derived cell lines in response to environmental perturbations and following transfection with sense- and anti-sense constructions of the OCP cDNAs. The OCPs are likely targets of auditory dysfunction -- either inherited or acquired. In fact, the location of the Ocp2 gene is identical to that of DFNAl, a familial postlingual deafness disorder.

Agency
National Institute of Health (NIH)
Institute
National Institute on Deafness and Other Communication Disorders (NIDCD)
Type
Research Project (R01)
Project #
2R01DC001414-04A1
Application #
2405874
Study Section
Hearing Research Study Section (HAR)
Project Start
1992-09-01
Project End
2002-06-30
Budget Start
1997-07-01
Budget End
1998-06-30
Support Year
4
Fiscal Year
1997
Total Cost
Indirect Cost
Name
Washington University
Department
Otolaryngology
Type
Schools of Medicine
DUNS #
062761671
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
Tan, Anmin; Tanner, John J; Henzl, Michael T (2008) Energetics of OCP1-OCP2 complex formation. Biophys Chem 134:64-71
Thalmann, Isolde (2006) Inner ear proteomics: a fad or hear to stay. Brain Res 1091:103-12
Thalmann, Isolde; Hughes, Inna; Tong, Benton D et al. (2006) Microscale analysis of proteins in inner ear tissues and fluids with emphasis on endolymphatic sac, otoconia, and organ of Corti. Electrophoresis 27:1598-608
Hughes, Inna; Thalmann, Isolde; Thalmann, Ruediger et al. (2006) Mixing model systems: using zebrafish and mouse inner ear mutants and other organ systems to unravel the mystery of otoconial development. Brain Res 1091:58-74
Henzl, Michael T; Thalmann, Isolde; Larson, John D et al. (2004) The cochlear F-box protein OCP1 associates with OCP2 and connexin 26. Hear Res 191:101-9
Yang, D; Thalmann, I; Thalmann, R et al. (2004) Expression of alpha and beta parvalbumin is differentially regulated in the rat organ of corti during development. J Neurobiol 58:479-92
Thalmann, Ruediger; Henzl, Michael T; Killick, Richard et al. (2003) Toward an understanding of cochlear homeostasis: the impact of location and the role of OCP1 and OCP2. Acta Otolaryngol 123:203-8
Thalmann, I (2001) Proteomics and the inner ear. Dis Markers 17:259-70
Thalmann, R; Thalmann, I (1999) Source and role of endolymph macromolecules. Acta Otolaryngol 119:293-6
Henzl, M T; Thalmann, I; Thalmann, R (1998) OCP2 exists as a dimer in the organ of Corti. Hear Res 126:37-46

Showing the most recent 10 out of 18 publications