The goal of the proposed work is to explore mechanisms of hearing loss induced by inflammatory cytokines in the cochlea. The work focused on the spiral ligament, because our recent work suggests that it 1) plays a critical role in cochlear fluid and ion homeostasis and 2) may be particularly susceptible to inflammatory processes. Type 1 fibrocytes are the most common cell type within the spiral ligament. They are part of a syncytium of cochlear supporting cells joined by intercellular connections called gap junctions. We have hypothesized that this gap junctional that this gap junctional system is essential for potassium ion recirculation from the organ of Corti to the stria vascularis and ultimately into endolymph, where a high potassium level is critical for normal high cell function. We have also found that type 1 fibrocytes contain high levels of the transcription factor NFkappaB, a protein that plays a key role in the acute phase inflammatory response of tissue to trauma or infections. In other tissues, inflammatory cytokines induced by NFkappaB can disrupt gap functional conductivity. Our working hypotheses is that inflammatory processes in the cochlea, arising from a wide array of disease states, induce cytokines in the spiral ligament, thereby blocking gap junctions between type 1 fibrocytes, depriving the stria vascularis of its potassium supply and producing profound sensorineural hearing loss. We will test this hypothesis by characterizing physiological and cytochemical responses of the cochlea following administration or induction of cytokines. We will measure changes in cochlear function by measuring evoke potentials and the endolymphatic potential and will use immunocytochemistry to document changes in cytochemical constituents of cochlear cells following the pharmacological experiments in order to determine the mechanisms underlying the cytokines' effects. The results may shed considerable light on the bases for sensorineural hearing loss in a variety of common, but poorly understood, otological disorders such as labyrinthitis, otosclerosis, genetic hearing losses involving gap junction proteins, and immune-mediated hearing loss. The proposed characterization of cytochemical substrates of inflammatory processes within the cochlea may help devise treatments or means of preventing hearing loss associated with these disorders.

Agency
National Institute of Health (NIH)
Institute
National Institute on Deafness and Other Communication Disorders (NIDCD)
Type
Research Project (R01)
Project #
5R01DC003929-05
Application #
6626875
Study Section
Special Emphasis Panel (ZRG1-IFCN-6 (01))
Program Officer
Donahue, Amy
Project Start
1999-01-01
Project End
2004-12-31
Budget Start
2003-01-01
Budget End
2004-12-31
Support Year
5
Fiscal Year
2003
Total Cost
$314,743
Indirect Cost
Name
Massachusetts Eye and Ear Infirmary
Department
Type
DUNS #
073825945
City
Boston
State
MA
Country
United States
Zip Code
02114
Adams, Joe C (2009) Immunocytochemical traits of type IV fibrocytes and their possible relations to cochlear function and pathology. J Assoc Res Otolaryngol 10:369-82
Adams, J C; Seed, B; Lu, N et al. (2009) Selective activation of nuclear factor kappa B in the cochlea by sensory and inflammatory stress. Neuroscience 160:530-9
McCullough, Brendan J; Adams, Joe C; Shilling, Dustin J et al. (2007) 3p-- syndrome defines a hearing loss locus in 3p25.3. Hear Res 224:51-60
Griffith, Andrew J; Yang, Yandan; Pryor, Shannon P et al. (2006) Cochleosaccular dysplasia associated with a connexin 26 mutation in keratitis-ichthyosis-deafness syndrome. Laryngoscope 116:1404-8
Zehnder, Andreas F; Kristiansen, Arthur G; Adams, Joe C et al. (2006) Osteoprotegrin knockout mice demonstrate abnormal remodeling of the otic capsule and progressive hearing loss. Laryngoscope 116:201-6
Arnold, Jelena S; Braunstein, Evan M; Ohyama, Takahiro et al. (2006) Tissue-specific roles of Tbx1 in the development of the outer, middle and inner ear, defective in 22q11DS patients. Hum Mol Genet 15:1629-39
Merchant, Saumil N; Burgess, Barbara; O'Malley, Jennifer et al. (2006) Polyester wax: a new embedding medium for the histopathologic study of human temporal bones. Laryngoscope 116:245-9
Resendes, Barbara L; Kuo, Sharon F; Robertson, Nahid G et al. (2004) Isolation from cochlea of a novel human intronless gene with predominant fetal expression. J Assoc Res Otolaryngol 5:185-202
Imamura, Shun-Ichi; Adams, Joe C (2003) Distribution of gentamicin in the guinea pig inner ear after local or systemic application. J Assoc Res Otolaryngol 4:176-95
Maison, Stephane F; Adams, Joe C; Liberman, M Charles (2003) Olivocochlear innervation in the mouse: immunocytochemical maps, crossed versus uncrossed contributions, and transmitter colocalization. J Comp Neurol 455:406-16

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