Regulation of Intestinal Transport

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DESCRIPTION, OVERALL (provided by applicant): The overall goal of this Program Project is to understand the mechanisms that underlie the dysregulation of electrolyte and solute transport in the intestine in the face of infection by enteric pathogens and inflammatory mediators. To this end, each of the four projects comprising this Program address one component of intestinal transport, either absorption, secretion, or passive paracellular movement. Project 1 will investigate the effects of an important enteric pathogen, enteropathogenic E. coli, on sodium absorption via Na+/H+ exchangers (NHEs); Project 2 will focus primarily on the transcriptional regulation of NHEs; Project 3 will investigate the role galanin receptor expression and activation on chloride secretion in response to enteric bacterial pathogens including Salmonella and EPEC; and Project 4 will address the effects of inflammatory mediators (LIGHT and IFN() on intestinal tight junction permeability. The individual projects are closely integrated with each other and the Cores. The three Cores (Core A - Imaging; Core B - Electrophysiology/Cell Culture; and Core C - Administration) were designed to fit the overall needs of the Program. A broad spectrum of approaches will be used to address a continuum of issues ranging from transcriptional regulation of key transporters and the influence of bacterial pathogens on each of the major modes of transport, to specific factors and signaling pathways involved in evoking such changes. The proposed projects will employ the same in vitro and in vivo model systems, cultured human intestinal epithelial monolayers and mouse models, and a broad range of experimental approaches to assess transport activity including electrophysiologic measurements, radioisotope and fluorometric ion transporter activity assays, cell imaging, molecular biological and biochemical techniques. Investigations will extend to select knock out mice in three of the projects. Together the projects, using cohesive and complementary approaches, address the regulation of the major components of intestinal transport (absorption, secretion, and tight junction permeability) under commonly encountered pathological conditions, intestinal inflammation and infectious diarrhea.