LIPID AND CHOLESTEROL ESTERASE IN NEONATAL GUT INTEGRITY

脂质和胆固醇酯酶对新生儿肠道完整性的影响

基本信息

批准号：
2889239
负责人：
PHILIP N HOWLES
金额：
$ 11.37万
依托单位：
UNIVERSITY OF CINCINNATI
依托单位国家：
美国
项目类别：
财政年份：
1995
资助国家：
美国
起止时间：
1995-08-03 至 2001-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/2889239
关键词：
apoptosis cell cycle congenital gastrointestinal disorder dietary lipid enzyme activity gastrointestinal epithelium gastrointestinal nutrient absorption laboratory mouse lipase lipid metabolism newborn animals nutrition related tag polymerase chain reaction southern blotting sterol esterase

项目摘要

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.

新生儿时期是广泛增长和成熟的时期肠绒毛上皮。成熟涉及膜的变化成分，粘膜渗透性和消化酶合成和分泌率。这个过程取决于肠内营养，是受新生儿饮食的脂质组成的影响很大。高脂肪管腔中的内容损害了绒毛上皮的完整性，新生儿上皮比成年人对这种侮辱更敏感。一个这种损害的极端例子是导致的坏死性小肠结肠炎主要是早产和低出生体重婴儿。虽然病因这种疾病尚不清楚，已经注意到配方奶粉的婴儿有母乳喂养婴儿患这种疾病的风险更高。目标该提议是为了检验胆汁刺激的脂肪酶的假设（BSSL）是母乳的主要蛋白质组成部分，可保护新生儿来自脂质诱导的肠道上皮损伤。牛奶BSSL是与胰腺胆固醇酯酶（CEH）相同，可以提供类似的在成熟胰腺中CEH生物合成发作之前的功能。初步的结果表明，BSSL/CEH抑制剂对与对照组相比，新生儿的绒毛上皮。此应用程序建议使用靶向破坏BSSL/CEH的小鼠菌株基因作为研究脂质诱导的新生儿损伤的动物模型绒毛上皮和肠道完整性的恢复原状。女子敲除小鼠将用于护理CEH（ - / - ）幼崽以检验假设 BSSL/CEH对于适当的新生儿肠道成熟是必需的。自然受伤和恢复原状的时间过程将由通过组织学和形态计量分析对照的上皮，受损和再生肠。初步研究的结果预测这些幼崽除非BSSL/CEH，否在他们的牛奶中提供。要测试的另一个假设是由于BSSL/CEH缺乏，对新生儿绒毛上皮的损害是由不完整脂质的中间代谢积累引起消化。这些未消除的脂质中间代谢物不完整脂质消化。这些未消除的脂质中间代谢物用作第二使者改变肠上皮的正常发育，在建立渗透性屏障之前。这些研究是对于确定增长的最佳营养要求和新生儿肠的发展，特别是在早产和低出生体重婴儿。