. The present work seeks to advance quantitative understanding of angular motion sensation by the semicircular canals, with specific attention to biophysics of transduction and signaling in crista hair bundles. Experiments will be done using a new transgenic mouse strain developed in our laboratory to image hair bundle deflection and calcium transients in stereocilia, in some cases through the intact ampulla without disrupting the membranous labyrinth.
The specific aims are motivated by preliminary data localizing stimulus-evoked calcium puncta almost exclusively at the tipse of tall stereocilia, data demonstrating upward movement of calcium puncta as the stimulus strength is increased, and data suggesting ultrafast calcium signaling from the transduction site to the cell body.
Specific Aim 1 will localize mechano-electrical transduction channels in the bundle using physiological stimulation, examine recruitment of channels as the stimulus strength is increased, and map the spatial distribution of transduction across the surface of the epithelium.
Specific Aim 2 will measure axial movements of stimulus evoked calcium puncta in stereocilia, and examine potential micromechanical and chemical-kinetic origins.
Specific Aim 3 will investigate ultrafast calcium signaling from the site of transduction at tips of hair bundles over a distance >40m to the cell body.
. Disorders afflicting angular motion sensation by the semicircular canals can be disabling, severely impairing mobility, balance, vision and the quality of life. This research is focused on key biophysical mechanisms essential for transduction and signaling in semicircular canal sensory hair bundles.
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