Abstract

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.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
5R01HD033920-08
Application #
6751990
Study Section
Nutrition Study Section (NTN)
Program Officer
Grave, Gilman D
Project Start
1996-12-13
Project End
2006-06-30
Budget Start
2004-07-01
Budget End
2006-06-30
Support Year
8
Fiscal Year
2004
Total Cost
$201,825
Indirect Cost

  Institution

Name
Baylor College of Medicine
Department
Pediatrics
Type
Schools of Medicine
DUNS #
051113330
City
Houston
State
TX
Country
United States
Zip Code
77030

  Publications

Yang, Chengbo; Yang, Xiaojian; Lackeyram, Dale et al. (2016) Expression of apical Na(+)-L-glutamine co-transport activity, B(0)-system neutral amino acid co-transporter (B(0)AT1) and angiotensin-converting enzyme 2 along the jejunal crypt-villus axis in young pigs fed a liquid formula. Amino Acids 48:1491-508
Yang, Chengbo; Albin, David M; Wang, Zirong et al. (2011) Apical Na+-D-glucose cotransporter 1 (SGLT1) activity and protein abundance are expressed along the jejunal crypt-villus axis in the neonatal pig. Am J Physiol Gastrointest Liver Physiol 300:G60-70
Burrin, Douglas G; Janeczko, Michael J; Stoll, Barbara (2008) Emerging aspects of dietary glutamate metabolism in the developing gut. Asia Pac J Clin Nutr 17 Suppl 1:368-71
Burrin, Douglas G; Stoll, Barbara (2007) Emerging aspects of gut sulfur amino acid metabolism. Curr Opin Clin Nutr Metab Care 10:63-8
Burrin, Douglas G; Stoll, Barbara; Guan, Xinfu et al. (2007) GLP-2 rapidly activates divergent intracellular signaling pathways involved in intestinal cell survival and proliferation in neonatal piglets. Am J Physiol Endocrinol Metab 292:E281-91
Janeczko, Michael J; Stoll, Barbara; Chang, Xiaoyan et al. (2007) Extensive gut metabolism limits the intestinal absorption of excessive supplemental dietary glutamate loads in infant pigs. J Nutr 137:2384-90
Riedijk, Maaike A; Stoll, Barbara; Chacko, Shaji et al. (2007) Methionine transmethylation and transsulfuration in the piglet gastrointestinal tract. Proc Natl Acad Sci U S A 104:3408-13
Stephens, John; Stoll, Barbara; Cottrell, Jeremy et al. (2006) Glucagon-like peptide-2 acutely increases proximal small intestinal blood flow in TPN-fed neonatal piglets. Am J Physiol Regul Integr Comp Physiol 290:R283-9
Lambert, Barry D; Filip, Rafal; Stoll, Barbara et al. (2006) First-pass metabolism limits the intestinal absorption of enteral alpha-ketoglutarate in young pigs. J Nutr 136:2779-84
Wang, Hui; Khaoustov, Vladimir I; Krishnan, Buvaneswari et al. (2006) Total parenteral nutrition induces liver steatosis and apoptosis in neonatal piglets. J Nutr 136:2547-52

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