LIPID AND CHOLESTEROL ESTERASE IN NEONATAL GUT INTEGRITY

新生儿期是一个广泛的增长和成熟的时间， 肠绒毛上皮成熟过程涉及细胞膜的变化 组成、粘膜渗透性和消化酶合成， 分泌率这一过程依赖于肠内营养， 受新生儿饮食中脂质成分的影响很大。高脂肪 管腔中的内容物损害绒毛上皮的完整性， 新生儿上皮细胞比成人对这种损伤更敏感。一个 这种损害的极端例子是坏死性小肠结肠炎， 主要是早产儿和低出生体重儿。虽然病因 这种疾病尚不清楚，但已经注意到，配方奶粉喂养的婴儿 母乳喂养的婴儿患这种疾病的风险更高。目标 这项建议的目的是检验胆盐刺激脂肪酶的假设， （BSSL）是母乳中的主要蛋白质成分，可保护新生儿 脂质导致的肠上皮损伤牛奶BSSL是 与胰腺胆固醇酯酶（CEH）相同， 在成熟胰腺中CEH生物合成开始之前的功能。初步 结果表明，BSSL/CEH抑制剂诱导了对 绒毛上皮的新生儿相比，对照组。本申请 建议使用具有BSSL/CEH靶向破坏的小鼠品系 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 基因敲除小鼠将用于喂养CEH（-/-）幼崽，以检验假设 BSSL/CEH是新生儿肠道正常成熟所必需的。性质 时间和伤害的过程和恢复将建立 对对照组的上皮进行组织学和形态计量学分析， 受损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 是在他们的牛奶里。另一个有待检验的假设是， 由于BSSL/CEH缺乏对新生儿绒毛上皮的损伤， 由不完全脂质的中间代谢物积累引起 消化.这些未消化的脂质中间代谢物不完全 脂质消化这些未消化的脂质中间代谢物作为 第二信使改变肠上皮的正常发育， 在渗透屏障建立之前。这些研究 重要的是确定最佳营养需求的增长和 新生儿肠道的发育，尤其是早产儿和低血糖儿 婴儿出生体重

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.