The experiments are designed to better understand the role that structural components such as intercellular tight junctions (TJ) and cytoskeletal elements underlying the plasma membrane play in the dynamic expression of permeability, barrier and transport characteristics of intestinal epithelia in health and in disease. To accomplish this goal, a variety of electron microscopic, fluorescence localization and electrophysiological experiments will be conducted in parallel. Information as to contributions by specific elements to these events to TJ permeability will be performed and a reductionistic model wherein the mechanism by which activation of Na-glucose cotransport results in altered TJ permeability studied. Second, the P.I. will examine how paracrine signals from non-epithelial cells in the epithelial compartment can alter the intestinal epithelial phenotype (including TJ permeability). These experiments will include studies aimed at better cataloging the extent to which the phenotype of model intestinal epithelia can be regulated. Third, the P.I. will utilize cell culture models of epithelial wound healing to explore potential contributors to, and mechanisms of regulation of, epithelial barrier restitution. Fourth, they will further explore the mechanisms by which cortical elements regulate transcellular movement of Cl- via effects on the activity of the basolateral transporter for Na, K, and Cl.
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