PHARMACOLOGICAL ANALYSIS OF IONIC BALANCE IN HAIR CELLS

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The proper functioning of hair cells, the sensory transducing cells of the auditory and vestibular systems, depends on proper ionic compositions both outside and inside those cells. Although much is known about the composition of fluids outside hair cells, little is known about ions inside hair cells or the processes that regulate them. Permanent damage to hair cells is a major cause of deafness. Most processes leading to injury of hair cells are poorly understood. In some circumstances, the natures of the insult and of the resulting injury suggest loss of ionic balance, and consequent loss of the hair cell's ability to regulate its volume, as possible causes of damage. The long-term objective of this project is to understand the cellular mechanisms that determine ionic balance in hair cells. this understanding would fill a major gap in knowledge about the normal physiology of hair cells. It would ultimately allow critical examination of the role of loss of ionic balance in the pathophysiology of hair cells. In this project, new information will be obtained about the cellular mechanisms of ionic balance in hair cells. In particular, electrically silent transporters and active ion transporters will be studied quantitatively in hair cells for the first time. Isolated hair cells will be subjected to pharmacological treatments that specifically affect mechanisms known to influence ionic balance in hair cells or in other cells. The ionic content of hair cells will be determined by electron probe microanalysis, providing both composition and net ion transport rates. Ionic activities (or "free" concentrations) will be determined by quantitative microfluorometry of ion-specific dyes, providing information about intracellular binding or sequestration of ions. Measurements of membrane potential will provide information about its influence on ionic transport during these treatments. By the end of the first three years, these studies should determine the quantitative importance of several major ionic channels, transporters, and pumps involved in ionic balance in hair cells. In later years, these findings will be extended to the situation in vivo, where different fluids bathe the apical and basolateral membranes of the hair cell. Ultimately, it will become possible to examine the role of ionic balance in specific issues in auditory physiology and pathophysiology, particularly with respect to temporary threshold shifts, acoustic trauma, ototoxicity, Meniere's disease, and aging.