Terminally differentiated, incapable of dividing, the sensory hair cells of the mammalian auditory organ must last a lifetime. This challenge, daunting in any tissue, is further complicated in the organ of Corti (OC) by the absence of vasculature, a highly positive electrical potential, and the continuous """"""""silent"""""""" K+ current. In this setting, even transient departures from the physiological norm result in hair cell death and consequent hearing loss. Ironically, the gene most commonly linked to hereditary deafness disorders (connexin 26, Cx26) is not expressed in the sensory cell, but rather in the supporting cell population, or epithelial support complex (ESC). Two common features unite the diverse cell types of the ESC - an elaborate epithelial gap-junction system (EGJS) and high-level expression of OCP1 and OCP2. Formed by hexagonal arrays of connexin molecules, gap-junctions facilitate movement of low molecular weight compounds - nutrients, metabolites, signaling molecules - between adjacent cells. As the severity of the Cx26 phenotype illustrates, disruption of this transport system has disastrous implications for sensory cell survival. Compelling preliminary evidence links OCP1 and OCP2 to regulation of the EGJS. The two most abundant proteins in the OC, OCP1 and OCP2 display homology to subunits of SCF E3 ubiquitin ligases. These multi-component, multi-functional complexes regulate a broad spectrum of biological processes, typically by targeting critical proteins for ubiquitination. Depending on the precise molecular details of the ubiquitin signal, the modified protein will experience one of several potential fates, including proteolytic destruction or sub-cellular relocation. The coincidence of OCP1-OCP2 expression with the boundaries of the EGJS suggests that the OCP1-OCP2 complex may participate in the ubiquitination of one or more connexin isoforms. This hypothesis is bolstered by the recent demonstration that OCP1 binds to Cx2.6 in vitro. The objective of the proposed research is to examine the functional significance of the OCP1-OCP2 complex and, in particular, its interrelationship with the EGJS. The multi-disciplinary project includes targeted disruption of the OCP1 gene, identification of additional OCP1 target proteins, and biochemical/biophysical characterization of the OCP1-OCP2 complex and OCPl-target complexes. This work will furnish insight into the physiological processes underlying preservation of hair cell function. It will advance our understanding of the system (Cx26) most commonly responsible for congenital hereditary hearing loss. Ultimately, the data from this project could provide a foundation for genetic and pharmacologic intervention in hearing disorders.

Agency
National Institute of Health (NIH)
Institute
National Institute on Deafness and Other Communication Disorders (NIDCD)
Type
Research Project (R01)
Project #
5R01DC001414-11
Application #
6984126
Study Section
Integrative, Functional and Cognitive Neuroscience 8 (IFCN)
Program Officer
Freeman, Nancy
Project Start
1992-09-01
Project End
2007-11-30
Budget Start
2005-12-01
Budget End
2007-11-30
Support Year
11
Fiscal Year
2006
Total Cost
$512,194
Indirect Cost
Name
Washington University
Department
Otolaryngology
Type
Schools of Medicine
DUNS #
068552207
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