EGF IN NEONATAL NECROTIZING ENTEROCOLITIS

新生儿坏死性小肠结肠炎（NEC）是早产儿最常见的胃肠道（GI）疾病，具有较高的发病率和死亡率，在美国每年有3000至4,000名婴儿受到影响。许多因素有助于NEC的发展，主要是早产、肠内喂养、感染因子和/或肠缺氧缺血。肠内喂养几乎总是NEC发展的先决条件。然而，NEC发病机制的确切机制知之甚少。在人类中，对926名新生儿进行的多中心试验表明，与母乳喂养的婴儿相比，配方奶粉喂养的婴儿NEC的发生率高出6-10倍。在动物实验中，母乳也可以预防NEC。这些发现刺激了对防止NEC的牛奶的各种成分的研究。表皮生长因子（EGF）是治疗NEC最有希望的候选药物之一。许多哺乳动物的乳汁含有高浓度的EGF。此外，母乳是新生儿在哺乳期EGF的主要来源。EGF在所有婴儿配方奶粉中都不存在。EGF可以加速胃肠道上皮细胞的愈合。另一种与EGF密切相关的肽是转化生长因子-α（TGF-α）。TGF-α是EGF相关肽家族的成员，与EGF具有显著的氨基酸序列同源性，相似的生物学效应，以及对相同受体- EGF受体（EGF-R）的高亲和力。EGF和TGF-α都存在于新生儿胃肠道中，它们对胃肠道上皮愈合过程的直接影响已经得到充分证实。由于TGF-α在大多数哺乳动物的乳汁中不存在，新生儿肠道TGF-α的主要来源是肠道内源性产生和胰腺分泌。最近，我们已经表明，乳源性EGF调节新生大鼠肠道TGF-α的合成。我们的长期目标是了解乳源性生物活性物质在NEC发病机制中的作用。这个建议的中心假设是，EGF将防止新生大鼠NEC的发展。乳鼠是研究NEC病因的最佳实验模型之一。我们的实验室有多年的人工饲养乳鼠的经验，因此我们有充分的条件来实现这一假设。目前，没有有效的治疗方法来预防NEC的发生。这个建议的基本原理是，EGF对新生儿在分子和细胞病理学水平的影响，必须了解之前，坏死性小肠结肠炎的充分治疗可以开发具体目标我将测试的假设，即牛奶中的EGF将防止发展NEC在乳鼠。具体目标II将测试的假设，肠外给予EGF将防止NEC和改善愈合的NEC在乳鼠。具体目标III将检验以下假设：用外源性EGF治疗NEC将上调患有NEC的乳鼠中EGF受体和TGF-α的肠表达。

Neonatal necrotizing enterocolitis (NEC) is the most common gastrointestinal (GI) disease of premature infants with excessive morbidity and mortality that afflicts 3 000 to 4,000 babies in the United States each year. Many factors contribute to the development of NEC, mainly prematurity, enteral feeding, infectious agents and/or intestinal hypoxia-ischemia Enteral feeding is nearly always a prerequisite for the development of NEC. However, the exact mechanism of NEC pathogenesis is poorly understood. In humans, multicenter trials with 926 neonates have shown that NEC is 6-10 times more common in formula-fed infants compared to those fed with human milk. In animal experiments, maternal milk also prevents NEC. These findings have stimulated the search for various components of milk that protects against NEC. Epidermal growth factor (EGF) is one of the most promising candidates for the treatment of NEC. Mammalian milk of many species contains high concentrations of EGF. Moreover, maternal milk is the major source of EGF for neonates during the suckling period. In contrast, EGF is absent in all commercial infant formulas. EGF accelerates healing of injured gastrointestinal epithelium. Another peptide closely related to EGF is transforming growth factor-alpha (TGF-alpha). TGF-alpha is a member of the family of EGF-related peptides, sharing with EGF significant amino acid sequence homology, similar biological effects, and high affinity to the same receptor - EGF- receptor (EGF-R). Both EGF and TGF-alpha are presented in the neonatal gastrointestinal tract and their direct effects on healing processes in the gastrointestinal epithelium are well established. Since TGF-alpha is absent in the milk of most mammals, the major source of intestinal TGF-a in neonates is intestinal endogenous production and pancreatic secretion. Recently, we have shown that milk-borne EGF modulates intestinal TGF-alpha synthesis in neonatal rats. Our long-term goal is to understand the role of milk-borne biologically active substances in the pathogenesis of NEC. The central hypothesis of this proposal is that EGF will prevent the development of NEC in newborn rats. One of the best experimental models to study the etiology of NEC are suckling rats. Our laboratory has many years of experience with artificial rearing of suckling rats and therefore we are well positioned to pursue this hypothesis. Currently, there is no efficient treatment to prevent the incidence of NEC. The rationale of this proposal is that the effect of EGF on neonates at the molecular and cellular pathology level must be understood before an adequate therapy of necrotizing enterocolitis can be developed Specific Aim I will test the hypothesis that milk-borne EGF will prevent the development of NEC in suckling rats. Specific Aim II will test the hypothesis that parenteral administration of EGF will prevent NEC and improve healing of NEC in suckling rats. Specific Aim III will test the hypothesis that the treatment of NEC with exogenous EGF will upregulate intestinal expression of EGF receptor and TGF-alpha in suckling rats with NEC.