The long term goal is to establish the minimal enteral nutrient requirements for the maintenance of intestinal growth in the TPN-fed neonate. The proposed studies will test three hypotheses: Hypothesis 1: There is an obligatory, and quantifiable, minimum level and optimum composition of nutrients that must be provided enterally to maintain normal neonatal intestinal growth. Hypothesis 2: The trophic effect of minimal enteral feeding on intestinal growth is mediated humorally by gastrin, but gastrin-mediated effects are dependent on a minimum level of enteral nutrients. Hypothesis 3: The trophic effects of both gastrin and enteral nutrients on intestinal growth are medicated via a common stimulation of mucosal ornithine decarboxylase (ODC) activity. These hypotheses will be tested using a neonatal pig model with the following specific aims:
Aim 1 : Quantify the minimal enteral nutrient requirement for maintenance of normal intestinal growth by a) direct in-vivo measurements of the first pass utilization of enterally administered U-13C-labeled amino acids and carbohydrate in full-fed pigs and b) by determining whether the provision of the level of enteral nutrients, as defined in part a), will maintain normal intestinal growth in neonatal pigs otherwise fed by TPN.
Aim 2 : Characterize the relative intestinal trophic effect of specific macronutrients (amino acids, carbohydrate and lipid) when provided at the minimal enteral level determined in Aim 1. Determine the effect of the physical form of the diet (elemental vs complex formula).
Aim 3 : Determine the role of circulating gastrin, in the absence of minimal enteral nutrients, or by inhibition of gastrin action, using the gastrin receptor antagonist, proglumide, in the presence of minimal enteral nutrients.
Aim 4 : Determine whether inhibition of ODC activity with chronic administration of difluoromethylornithine blocks the trophic effect of either gastrin or minimal enteral nutrients on intestinal growth in TPN-fed neonatal pigs. Methods used to quantify intestinal growth and cellular proliferation in all of these studies will include mass estimates (protein and DNA, in vivo protein synthesis (2H3/13C1-Leu incorporation), in vivo crypt cell proliferation index (BrdU labeling), villus morphometry, and IFG-I mRNA expression. The care of TPN-fed preterm infants imposes a significant health care cost in the United States. This proposal will establish the enteral nutrient requirements for normal intestinal growth in the TPN-fed neonatal pig, and thus, with appropriate scaling, provide a basis for more rational development of enteral feeding strategies and enteral nutrient needs in TPN-fed preterm infants.
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