Hearing loss is one of the most common forms of sensory deficits affecting humans, and the military is one of the professions that is most affected. Further, there is no medical treatment for hearing loss. Many factors contribute to hearing loss including genetic defects, environmental factors (noise and ototoxic drugs), and aging. One of the major causes of hearing loss is the permanent loss of hair cells, the inner ear sensory cells that detect sounds. Unlike non-mammalian species, such as chick and fish, in which hair cells can be spontaneously regenerated with hearing recovered, the mammalian inner ear lacks the capacity to regenerate hair cells, making hearing loss permanent.

One of the most promising ways to development a potential therapy for hearing loss is through hair cell regeneration. Tremendous progress has been achieved on hair cell regeneration over the years. However, most of the work has been done in the immature inner ear, whereas the inner ear of a human newborn is fully mature. Thus, to use hair cell regeneration for functional recovery of hearing it is necessary to show that hair cell regeneration can be achieved in the mature inner ear.

Our proposal aims to achieve hair cell regeneration in the fully mature mammalian inner ear and hearing recovery from a noise-induced hearing loss mouse model. We will use cutting-edge technology including reprogramming to re-set the biological clock of the mature inner ear and to turn them into a stage reminiscent of the young inner ear, so the mature inner ear cells can regain the capacity to regenerate hair cells. This is achieved by transient co-activation of two important factors, c-Myc and Notch1, in the adult inner ear. With this approach, fully mature inner ear cells can divide to increase cell numbers, and they can, further, be converted into hair cells. This approach provides an exciting opportunity to achieve hair cell regeneration reliably in the adult inner ear, with the potential to be developed to treat deafness.

If our project is successful, we should be able to regenerate hair cells in the fully mature inner ear, with the implication that such a strategy can eventually be used to regenerate hair cells for hearing recovery in the human inner ear that will greatly benefit military Service members and Veterans. If we can achieve hearing recovery in our project, we could extend the study to include other forms of deafness due to toxicity of ototoxic drugs as well as aging, which should inform us about the general application of our approach. The study is preclinical, and major efforts will be needed to develop it for clinical study. The study, however, should serve as the foundation for future work toward clinical application.

One major benefit of the study is to provide a new way to address hair cell regeneration in the adult inner ear. Successful completion of the study should enable other researchers to adapt a similar route and identify new pathways in reprogramming of the adult inner ear, which combined should eventually lead to accelerated progress toward clinical application using hair cell regeneration.