This application seeks continued support for a broad program of research directed towards elucidation of the mechanisms that control and regulate electrolyte transport across cell membranes. Investigators will use a wide variety of approaches and techniques to evaluate (1) molecular mechanisms determining passive and active translocation across individual cell membranes and across epithelia, (2) the relationship between transport and cell metabolism and (3) electrical manifestation of ion transport. In addition to physiological transport studies, pathological transport defects and the site and mechanism of action of drugs and of hormones will also be investigated. Transport will be studied on isolated enzyme systems in vitro (ATPase), in single cells (red blood cells, neurospora), isolated epithelia (renal tubule, intestinal mucosa, amphibian and mammalian bladder) and on organ systems (kidney, liver and intestine). Vesicular preparations of epithelia and transport in cell cultures will also be evaluated. A wide spectrum of approaches will be used. These will include measurements of transport rates, tracer fluxes, fluorescence, cell pH, cell ion activities and electron probe analysis of elements. In addition, electrophysiological and immunocytological techniques will be employed. Finally, we shall continue the use of electron-microscopic methods to investigate the correlation between cell membrane structure and electrolyte and fluid transport.
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