Hearing Restoration in Mouse Models with Noise-induced Hearing Loss.

摘要

As a long-term goal, we aim to develop therapeutics which would restore hearing in navy servicemen who are suffering from noise induced hearing loss (NIHL). Our central hypothesis is that inactivation of pl6lnk4a or other cell cycle inhibitors in mammalian supporting cells (SCs) will allow them to respond to acoustically damaged hair cells (HCs) and to reenter the cell cycle; subsequently the introduction of Atohl will cause the newly created SCs to transdifferentiate into HCs. To test this hypothesis, we propose to develop mouse models and small molecule inhibitors to: Aim 1) characterize the regenerative capacity of SCs in mice after noise-induced damage and transient or permanent inactivation of p 16Ink4a; Aim 2) assess the ability of Atohl to transdifferentiate SCs into HCs after noise-induced damage in mice. Our studies will provide a basis for future clinical trials using cell cycle inhibitory and HC-differentiation promoting drugs to restore hearing in humans. Since the award, we have modified Aim 1 to include screening of p27Kipl inhibitors; this is based on our recent exciting results of acute inactivation of p27Kipl in neonatal SCs.