MINIMAL ENTERAL NUTRIENT REQUIREMENTS IN NEONATES

长期目标是量化肠内营养。 对新生儿肠道生长和功能的要求并确定 调节肠道营养反应的细胞机制。这项工作 拟议研究中概述的将检验四个假设：1)维持 GLP-2在肠道喂养典型水平的循环浓度 TPN喂养的新生猪的肠道生长和结构将得到恢复。2) 在这个生理范围内，GLP-2强烈地激活细胞信号 导致抑制肠道蛋白分解和细胞凋亡的途径， 这些细胞过程是肠道的主要媒介 GLP-2的营养效应。3)维持GLP-2的生理水平 在一段时间内TPN会向上调节肠道的乳糖容量 消化和葡萄糖吸收。4)在子宫里，胎儿的肠子 对GLP-2无反应。这些假设将使用TPN-Feed， 初乳剥夺的新生猪模型：目的1：量化 GLP-2对肠道质量和形态的生理性剂量效应。目标2： 测定肠道蛋白水解酶基因(溶酶体、 泛素-蛋白酶体和钙激活)与细胞凋亡活性 猪的信号转导途径中间产物(Pl-3Kinase/PKB、Bcl2、Caspase) 给予生理剂量的GLP-2，持续3、6或48小时。此外，为了测量 肠道蛋白质合成和蛋白水解酶的体内动力学 GLP-2治疗6、48和168小时后门脉13C-苯丙氨酸的平衡 输液。目的3：测定刷缘和基底膜葡萄糖 乳糖酶SGLT-1和SGLT-1的转运活性及丰度和合成速率 GLUT2，基于~(13)C/H-亮氨酸掺入动力学 生理剂量GLP-2，连服7d。此外，还可以测量其体内动力学。 肠道乳糖消化和葡萄糖吸收，以门脉为基础 给予生理剂量GLP-2的猪半乳糖和13C-葡萄糖的平衡 七天。目标4：确定肠道营养(蛋白质代谢/细胞 周转率)和功能(乳糖酶/葡萄糖转运活性)对 胎儿(宫内)和新生猪之间给予GLP-2的生理剂量 胎龄106天和112天。

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.