The long-term objectives are to understand the cellular mechanisms of mechanotransduction in auditory hair cells and the factors underlying the cochlea's tonotopic organization. Experiments will focus on the role of intracellular Ca 2+ in regulating transducer channel adaptation and hair bundle mechanics. Hair cell responses will be measured in the isolated cochleas of both reptiles and mammals and will be combined with intracellular Ca 2+ imaging.
Specific aims are: (1) to record transducer currents in rodent hair cells before and after the onset of hearing, documenting the changes in properties with maturation and with cochlear location. (2) to characterize single transducer channels and investigate their modulation by Ca 2+ and variation with frequency. Comparison of turtle and rodent results may illustrate the evolution of transducer channel properties; (3) to measure the mechanical properties of hair cell stereociliary bundles and search for spontaneous and active bundle motion in mammalian outer hair cells. The interaction between active bundle motion and outer hair cell contractility will be used to assess the roles of the two processes in amplification and tuning in the mammalian cochlea. (4) to measure the distribution of K+ channel slice variants in the turtle cochlea from both single channel recording and immunolabeling for specific channel isoforms. The results may provide insight into the origin of the cochlea's tonotopic organization. (5) to measure and alter Ca 2+ concentration in hair bundles and relate it to control of transducer channel activation and active hair bundle motion. The contributions of Ca 2+ buffering and uptake into intracellular compartments, especially the mitochondria, to limit Ca 2+ transients will be studied. Since hair cells experience large Ca 2+ loads, disturbance of Ca 2+ homeostasis may be a leading cause of cell death. Ca 2+ modulation of transducer channels is probably common to all hair cells and may be the conduit of irreversible damage during noise exposure, poisoning with ototoxic agents or aging. Loss of hearing with aging or over-stimulation is often restricted to high frequencies and linked to degeneration of hair cells at the base of the cochlea. The work will address reasons for the differential sensitivity by mapping number and properties of transducer channels with cochlear location. ? ?
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