LIPID AND CHOLESTEROL ESTERASE IN NEONATAL GUT INTEGRITY

新生儿期是婴儿广泛生长和成熟的时期。 肠绒毛上皮。成熟期涉及细胞膜的变化。 组成，粘膜通透性，消化酶合成和 分泌率。这一过程依赖于肠内营养，并且 在很大程度上受新生儿饮食中脂肪成分的影响。高脂肪 管腔中的内容损害了绒毛上皮的完整性，并且 新生儿的上皮细胞对这种侮辱比成年人更敏感。一个 这种损害的极端例子是坏死性小肠结肠炎，它影响 主要是早产儿和低出生体重儿。虽然该病的病因 这种疾病还不清楚，人们已经注意到，配方奶喂养的婴儿 母乳喂养的婴儿患这种疾病的风险更高。目标是 这一提议的目的是检验胆盐刺激脂肪酶 (BSSL)是母乳的主要蛋白质成分，可以保护新生儿 由脂质引起的肠道上皮损伤。牛奶牛腿肉是 与胰腺胆固醇酯酶(CEH)相同，可能起类似的作用 成熟胰腺CEH生物合成开始前的功能。初步 结果表明，BSSL/CEH抑制剂对细胞有明显的损伤作用 新生儿绒毛上皮细胞与对照组比较。此应用程序 建议使用一种小鼠品系，靶向破坏BSSL/CEH 基因作为研究新生儿脂质损伤的动物模型 绒毛上皮和肠道完整性的恢复。女性CEH 基因敲除小鼠将被用来喂养CEH(-/-)幼鼠，以检验这一假说 BSSL/CEH是新生儿肠道正常成熟所必需的。大自然 受伤和恢复原状的时间进程将通过以下方式确定 对对照组的上皮进行组织学和形态计量学分析， 受损的和再生的肠道。初步研究结果 预测这些幼崽将遭受严重的粘膜损伤，除非BSSL/CEH 是在它们的乳汁中提供的。另一个需要检验的假设是 BSSL/CEH缺乏症对新生儿绒毛上皮的损伤 由不完全脂类的中间代谢产物堆积引起 消化。这些未消化的脂质中间代谢产物是不完全的 脂肪消化。这些未消化的脂质中间代谢物作为 第二信使改变肠道上皮的正常发育， 在建立渗透性屏障之前。这些研究是 在确定生长和生长所需的最佳营养需求方面很重要 新生儿肠道发育，尤其是早产儿和低产儿 出生体重婴儿。

The neonatal period is a time of extensive growth and maturation of the intestinal villus epithelium. The maturation involves changes in membrane composition, mucosal permeability, and digestive enzyme synthesis and secretion rates. This process is dependent on enteral nutrition and is greatly affected by the lipid composition of the neonatal diet. High fat content in the lumen compromises villus epithelium integrity, and the neonatal epithelium is more sensitive than the adults to this insult. An extreme example of this damage is necrotizing enterocolitis which affects primarily preterm and low birth weight infants. Although the etiology of this disease is not clear, it has been noted that formula-fed infants have a higher risk that breast-fed infants of developing this disease. The goal of this proposal is to test the hypothesis that bile salt-stimulated lipase (BSSL), a major protein constituent of breast milk, protects the neonate from lipid-induced injury of the gut epithelium. The milk BSSL is identical to pancreatic cholesterol esterase (CEH) and may serve a similar function before onset of CEH biosynthesis in mature pancreas. Preliminary results show that a BSSL/CEH inhibitor induced significant damage to the villus epithelium of neonates as compared to controls. This application proposes to use a mouse strain with targeted disruption of the BSSL/CEH gene as an animal model to study lipid-induced injury of the neonatal villus epithelium and the restitution of gut integrity. Female CEH knockout mice will be used to nurse CEH (-/-)pups to test the hypothesis that BSSL/CEH is necessary for proper neonatal gut maturation. The nature and time course of the injury and restitution will be established by analyzing histologically and morphometrically the epithelium of control, damaged, and regenerating intestine. Results of preliminary studies predict that these pups will sustain severe mucosal injury unless BSSL/CEH is provided in their milk. An additional hypothesis to be tested is that damage to the villus epithelium of neonates, due to BSSL/CEH deficiency, is caused by accumulation of intermediate metabolities of incomplete lipid digestion. These undigested lipid intermediate metabolites of incomplete lipid digestion. These undigested lipid intermediate metabolites serve as second messengers to alter normal development of the intestinal epithelium, before establishment of the permeability barrier. These studies are important in defining optimal nutritional requirements for growth and development of the neonatal intestine, especially in premature and low birth weight infants.