The cochlea receives its main blood supply from the basilar artery, via the anterior inferior cerebellar artery and the spiral modiolar artery. It is of clinical importance to understand the mechanisms that regulate cochlear blood flow, since many hearing disorders, such as sensorineural hearing loss, acute acoustic trauma, noise-induced hearing loss, tinnitus, Meniere's disease and presbyacusis may be caused or aggravated by localized vasospasms that pathologically limit cochlear blood flow and cause transient ischemic events. Calcium is the major focus of this proposal since it is obligatory for vasoconstrictions. The cytosolic Calcium concentration in vascular smooth muscle cells is tightly controlled and effectively compartmentalized into pools that mediate vasoconstriction and pools that mediate vasodilation. Calcium that mediates vasoconstriction is commonly released as Calcium waves and calcium that mediates vasodilations is commonly released as Calcium sparks. In general, the cytosolic Calcium concentration is controlled via export/import across the plasma membrane and in and out of cytosolic Calcium stores. The extracellular Calcium concentration may not only serve as a simple reservoir for Calcium but constitute an important paracrine messenger that has so far received little attention. For this proposal we have targeted two major areas focused on Calcium as it relates to the cellular regulation of cochlear blood flow. Most experiments will be performed using an isolated in vitro superfused preparation of the spiral modiolar artery. Vascular diameter will be measured by videomicroscopy and cytosolic Calcium by confocal microfluorometry. The presence of receptors and ion channels will be determined by a combination of a pharmacological approach using functional assays, a molecular biological approach and a protein biochemical approach.
Under Specific Aim 1, we will determine whether different modes of Calcium release from cytosolic stores cause vasodilations and constrictions, respectively.
Under Specific Aim 2 we will determine how smooth muscle cells sense the extracellular Calcium concentration. Completion of these Specific Aims will greatly enhance our understanding of the cellular mechanisms of cochlear blood flow regulation, which is a necessary prerequisite for the rational design of pharmacological interventions needed to combat a multitude of hearing disorders. ? ? ?
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