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.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
2R01HD033920-04A1
Application #
6197889
Study Section
Nutrition Study Section (NTN)
Program Officer
Grave, Gilman D
Project Start
1996-12-13
Project End
2005-06-30
Budget Start
2000-07-01
Budget End
2001-06-30
Support Year
4
Fiscal Year
2000
Total Cost
$201,825
Indirect Cost
Name
Baylor College of Medicine
Department
Pediatrics
Type
Schools of Medicine
DUNS #
074615394
City
Houston
State
TX
Country
United States
Zip Code
77030
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