Cochlear Homeostasis

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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.