MECHANISMS OF INTESTINAL CELL MIGRATION

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DESCRIPTION (adapted from the application) Currently, the only available treatments for infants with infectious diarrhea are oral rehydration and antibiotics. Previous work focused on amino acids, specifically glutamine (GLN) and arginine (ARG), because of their cost, safety, proabsorptive effect, and capacity to promote intestinal repair. Of the two amino acids, ARG was found to be more effective in enhancing restitution, the initial stage of intestinal repair during which the columnar cells migrate to cover basement membrane. ARG synergized with fetal bovine serum or a bovine serum concentrate to enhance migration of wounded intestinal epithelial monolayers and to facilitate recovery of transepithelial electrical resistance of acutely injured pig ileum. The aims of the current proposal are to study the mechanisms of these complementary effects of ARG and serum. The central hypothesis is that after injury serum (and bovine serum concentrate) provide growth factors which synergize with arginine-derived nitric oxide and polyamines to potentiate molecular signaling during migration and restitution. Focal adhesions are multiprotein complexes in extending lamellipodia during epithelial cell migration. Several kinases are activated by protein tyrosine phosphorylation at focal adhesions during intestinal cell migration. We will measure the expression and activity of focal adhesion kinase (FAK), calcium-dependent tyrosine kinase (CADTK, also called PYK-2), extracellular-related kinases (ERK's -1 and -2), and p70s6k during intestinal cell migration, comparing cells and tissues treated with ARG + serum. Active growth peptides in serum will be identified and quantified. We will determine if ARG potentiates serum growth factor signaling or activates separate signaling pathways during migration.