The aim of this research proposal is to understand the relationship between the passive and active tuning properties of the cochlear partition and to develop techniques that can be used to change the cochlear frequency map. The mammalian cochlea is tuned tonotopically based upon systematic changes in the passive mechanics of the cochlear partition. Outer hair cell (OHC) electromotility is an active component of the cochlear partition that adds energy to the traveling wave, sharpens and shifts cochlear tuning, and imparts exquisite hearing sensitivity and frequency selectivity. We hypothesize that changing the biomechanical properties of the cochlear partition will modulate the sharpness, sensitivity, and resonant frequency map of cochlear tuning. In the proposed research, in vivo and in vitro experiments designed to manipulate both the passive and the active components of the cochlear partition will be performed using the guinea pig cochlea. In order to modulate the passive mechanics, the basilar membrane will be displaced either by a stiffprobe or paramagnetic beads controlled by a magnetic field, or stiffened by laser photocoagulation. In order to modulate the active mechanics, specific sites within the OHC necessary for normal electromotility will be targeted using drugs administered via perilymphatic perfusion. The targets to be modulated include OHC turgor pressure, cytoskeletal stiffness, membrane fluidity, anion concentration, and the prestin motor protein. Basilar membrane motion will be measured using a laser doppler vibrometer. Other measures of cochlear function to be monitored include the compound action potential, distortion product otoacoustic emissions, the cochlear microphonic, and the endolymphatic potential. These data will be combined with histologic study of the temporal bones and computer modeling analysis to understand the impact of experimental manipulations. In addition to pursuing this research, the candidate will use this time and funding provided by this grant to develop into an independent clinician-scientist. This will involve both structured didactic activities as well as close interactions with two mentors and several collaborators. The long-term goal of the candidate is to extend this line of translational research to develop therapeutic interventions for patients with noise-induced and age-related sensorineural hearing loss.
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