PROJECT SUMMARY Physiological recordings and measurements of otoacoustic emissions (OAEs) in transgenic mice have helped to characterize the effects of genetic mutations of the tectorial membrane (TM) on cochlear function. However, current understanding of the role of the TM in mammalian hearing mechanics remains limited. This research aims to elucidate the role of the TM in hearing mechanics using computational models of wild-type and transgenic mice. More specifically, the proposed research focuses on the role of the TM in the active feedback mechanism called cochlear amplifier that is necessary to achieve sharp tuning and high sensitivity in response to low level sounds. Specific Aim 1 seeks to determine how genetic mutations of the TM alter mechanical coupling of outer hair cells. Specific Aim 2 will establish how changes in the mechanical properties of the TM in transgenic mice affect cochlear tuning and OAE-based measures of cochlear tuning. Specific Aim 3 will investigate the underlying mechanism for the enhancement of some types of OAEs that has previously been reported in some transgenic mice. In order to accomplish the objectives of this research, we will carefully model the effects of the mutations on the structure, anatomy, and mechanical properties of the TM and will predict the effect of the mutations on cochlear mechanics and OAEs by using a physiologically-based computational model of the murine cochlea. Theoretical models will be validated using published experimental data and new experimental data that will be provided by our collaborators. Furthermore, we will make theoretical predictions that will be experimentally tested by our collaborators. The results of this research will demonstrate that our unique virtual laboratory for hearing mechanics that includes details about cochlear micromechanics and TM mechanics constitutes a com- prehensive framework that can explain invasive physiological data as well as noninvasive OAE measurements. If successful, this research will help to better diagnose and treat hearing impairment and auditory disorders caused by genetic abnormalities of the TM, since some mutations of the proteins expressed in the TM have been linked to human hereditary deafness. The results of this research will also facilitate the design of hearing aids and cochlear implants by helping to extract more information from noninvasive OAE measurements.