Project Abstract Hearing impairment is one of the most prevalent human disabilities. For patients with severe and profound sensorineural hearing loss (SNHL) beyond the range that could be helped by amplification-based external devices (e.g., hearing aids or personal listening devices), currently the only effective treatment is the cochlear implant (CI). Research communities have spent large amounts of effort and money to improve the quality and lower the cost of CIs, as well as finding alternative treatments that do away with the need for a prosthesis altogether. In this R21 we propose a high-risk and potentially high-reward approach to restore hearing without using any implanted prosthetic device that could produce a feasible sound perception quality predicted to be significantly better than that theoretically-achievable by CIs. We hypothesize that mammalian hearing can be restored without any prosthetic device if the spiral ganglion neurons (SGNs) can be transformed to directly respond to basilar membrane vibration. We believe our approach may have a better chance of translational success than many gene-based and cell-based therapies currently under investigation, because its requirements for cellular survival and cochlear integrity are similar to that of CIs. We will perform feasibility studies in this R21 to characterize candidates of membrane-based mechano- sensitive channels (MSCs) by testing naturally-occurring as well as engineered MSCs in vitro. We will then virally express the identified membrane-based MSCs in SGNs of mouse models of common human deafness caused by connexin26 and connexin30 null mutations, in order to examine if acoustical hearing is restored.