EGF IN NEONATAL NECROTIZING ENTEROCOLITIS

EGF 在新生儿坏死性小肠结肠炎中的作用

• 批准号: 6224356
• 负责人: BOHUSLAV DVORAK
• 金额: $ 27.27万
• 依托单位: UNIVERSITY OF ARIZONA
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-02-15 至 2005-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6224356
• 关键词: chemoprevention; electron microscopy; endotoxins; enzyme activity; epidermal growth factor; gastrointestinal disorder chemotherapy; gene induction /repression; growth factor receptors; intestine disorder; laboratory rat; milk; myeloperoxidase; newborn animals; nonhuman therapy evaluation; nutrition related tag; parenteral feedings; polymerase chain reaction; receptor expression; transforming growth factors

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.

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，发病率和死亡率极高，美国每年有 3,000 至 4,000 名婴儿受到影响。许多因素导致 NEC 的发生，主要是早产、肠内喂养、传染源和/或肠道缺氧缺血。肠内喂养几乎总是 NEC 发生的先决条件。然而，NEC 发病机制的确切机制尚不清楚。在人类中，对 926 名新生儿进行的多中心试验表明，配方奶喂养的婴儿中 NEC 的发生率是母乳喂养婴儿的 6-10 倍。在动物实验中，母乳也能预防 NEC。这些发现激发了人们对牛奶中可预防 NEC 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都含有高浓度的 EGF。此外，母乳是新生儿哺乳期EGF的主要来源。相比之下，所有商业婴儿配方奶粉中均不含 EGF。 EGF 加速受损胃肠道上皮的愈合。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相关肽家族的一员，与EGF具有显着的氨基酸序列同源性、相似的生物学作用以及与同一受体——EGF-受体(EGF-R)的高亲和力。 EGF 和 TGF-α 均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得到充分证实。由于大多数哺乳动物的乳汁中不存在 TGF-α，因此新生儿肠道 TGF-α 的主要来源是肠道内源性产生和胰腺分泌。最近，我们发现乳源性 EGF 可以调节新生大鼠肠道 TGF-α 的合成。我们的长期目标是了解乳源生物活性物质在 NEC 发病机制中的作用。该提案的中心假设是 EGF 将阻止新生大鼠 NEC 的发生。研究 NEC 病因的最佳实验模型之一是乳鼠。我们的实验室在人工饲养乳鼠方面拥有多年的经验，因此我们有能力追求这一假设。目前，尚无有效的治疗方法来预防 NEC 的发生。该提案的基本原理是，在开发出适当的坏死性小肠结肠炎治疗方法之前，必须在分子和细胞病理学水平上了解 EGF 对新生儿的影响。 具体目标 I 将检验奶源 EGF 将预防乳鼠 NEC 发展的假设。具体目标 II 将检验以下假设：肠外施用 EGF 将预防乳鼠 NEC 并改善 NEC 愈合。具体目标 III 将检验以下假设：用外源 EGF 治疗 NEC 将上调 NEC 乳鼠肠道内 EGF 受体和 TGF-α 的表达。