The post mitotic nature of cochlear sensory and non-sensory cells requires protection against apoptotic processes for lifetime maintenance of normal cochlear function. The diverse specializations of cochlear cells dictates that their anti-apoptotic pathways, which respond to cell specific stresses are correspondingly diverse. In the past funding period, we accumulated evidence that spiral ligament cells' responses to cochlear stresses play a key role in protection of the entire organ. A major player in anti-apoptotic pathways is a family of transcription factors known as NFkappaB (NFkappaB). We used a transgenic reporter mouse to show that it is spiral ligament fibrocytes, not cells within the organ of Corti, that show robust NFkappaB activation in response to noise exposure. Similarly, we showed that the receptor for a growth factor (GDNF), known to protect sensory cells from noise and ototoxic drugs, is not present on hair cells, but in spiral ligament fibrocytes, where it's expression is robustly up-regulated following a non-traumatic noise exposure known to protect the ear from subsequent acoustic injury. We hypothesize that noise-induced up-regulation of this receptor is downstream of NFkappaB activation, and that this up-regulation in the spiral ligament is key to the induction of cochlear protection via pre-exposure to noise stressors, and to the age-related difference in vulnerability to noise seen in normal-hearing CBA/CalphaJ mice. In this proposal, we test these hypotheses (1) by using a well-established mouse model of noise-induced protection from noise trauma to compare the time course of induction and reduction of protection with the time course of noise-induced changes in cochlear expression and translation of NFkappaB, the GDNF receptor, and other related stress genes, (2) by testing the effects of selectively blocking noise-induced NFkappaB activation in spiral ligament fibrocytes using a transgenic mouse in which a key upstream activator of NFkappaB has been eliminated and (3) by comparing noise-induced changes in cochlear expression and translation of NFkappaB, the GDNF receptor, and other related stress genes in vulnerable young mice vs. resistant middle-aged mice. The results of these studies will clarify the role of NFkappaB, an important arm of the complex cascade of anti-apoptotic stress-induced gene expression pathways, in the induction of cochlear protected states and will also add to our understanding of the functional role(s) of the spiral ligament fibrocytes, which are now known to be a major locus of cochlear histopathology in a variety of inherited and acquired types of deafness.

Agency
National Institute of Health (NIH)
Institute
National Institute on Deafness and Other Communication Disorders (NIDCD)
Type
Research Project (R01)
Project #
2R01DC003929-06A1
Application #
6928074
Study Section
Auditory System Study Section (AUD)
Program Officer
Donahue, Amy
Project Start
1999-01-01
Project End
2010-03-31
Budget Start
2005-04-01
Budget End
2006-03-31
Support Year
6
Fiscal Year
2005
Total Cost
$332,200
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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