The long-term goals are to quantify the enteral nutrient requirements for neonatal intestinal growth and function and identify the cellular mechanisms that mediate the intestinal trophic response. The work outlined in the proposed studies will test four hypotheses: 1) Maintaining the circulating concentration of GLP-2 at a level typical of the enterally fed pigs, will restore intestinal growth and structure in TPN-fed neonatal pigs. 2) Within this physiological range, GLP-2 acutely activates cellular signaling pathways that lead to a suppression of intestinal proteolysis and apoptosis, and that these cellular processes are the primary mediators of the intestinal trophic effects of GLP-2. 3) The maintenance of physiological levels of GLP-2 during a period of TPN will up regulate the intestinal capacity of lactose digestion and glucose absorption. 4) In utero, the fetal intestine is unresponsive to GLP-2. These hypotheses will be tested using a TPN-fed, colostrum-deprived, neonatal pig model with these aims: Aim 1: Quantify the physiological dose response of GLP-2 on intestinal mass and morphology. Aim 2: Determine the intestinal expresson of protease genes (lysosomal, ubiquitin-proteasomal, and calcium-activated) and activity of apoptotic signaling pathway intermediataes (Pl-3 kinase/PKB, Bcl-2, caspases) in pigs infused with physiological GLP-2 dose for 3, 6, or 48 hours. Also, to measure the in vivo kinetics of intestinal protein synthesis and proteolysois, based on the portal balance of 13C-phenylalanine, after 6, 48, and 168 hours of GLP-2 infusion. Aim 3: Determine the brush-border and basolateral membrance glucose transport activity and the abundance and synthesis rate of lactase, SGLT-1 and GLUT2, based on the kinetics of 13C/H-leucine incorporation, in pigs given a physiological GLP-2 dose for 7 days. Also, measure the in vivo kinetics of intestinal lactose digestion and glucose absorption, based on the portal balance of galactose and 13C-glucose, in pigs given physiological GLP-2 dose for 7 days. Aim 4: Determine the intestinal trophic (protein metabolism/cell turnover) and functional (lactase/glucose transport activity) responsiveness to a physiological GLP-2 dose given to fetal (in utero) and newborn pigs between 106 and 112 days gestational age.

R01HD033920

1996-12-13

2006-06-30