| Popis: |
Noise induced hearing loss (NIHL) affects over ten million adults in the United States, and there is no biological treatment to restore endogenous function after damage. We hypothesized that activation of signaling from ERBB2 receptors in cochlear supporting cells could mitigate NIHL damage. We used the Tet-On genetic expression system to drive a constitutively active variant of ERBB2 (CA-ERBB2) in cochlear supporting cells three days after permanent noise damage in young adult mice. Hearing thresholds were assessed with auditory brainstem response tests prior to noise damage, and hearing recovery was assessed over a three month period. We evaluated supporting cell proliferation, inner and outer hair cell (IHC and OHC) survival, synaptic preservation, and IHC cytoskeletal alterations with histological techniques. Mice harboring CA-ERBB2 capability had similar hearing thresholds to control littermates prior to and immediately after noise exposure, and incurred similar levels of permanent hearing loss. Two and three months after noise exposure, CA-ERBB2+ mice demonstrated a partial but significant reversal of NIHL threshold shifts at the lowest frequency tested, out of five frequencies (n=19 total mice, p=0.0015, ANOVA). We also observed improved IHC and OHC survival (n=7 total cochleae, p=5 × 10 −5 , Kruskal-Wallis rank sum test). There was no evidence for sustained supporting cell proliferation. Some mortality was associated with doxycycline and furosemide treatments to induce the Tet-ON system. These data suggest that ERBB2 signaling in supporting cells promotes HC repair and some functional recovery. Funded by NIH R01 DC014261, and grants from the Schmitt Foundation and UR Ventures. |
