Mechanism of EGF-Mediated Reduction of NEC

EGF 介导的 NEC 减少机制

• 批准号: 7257893
• 负责人: BOHUSLAV DVORAK
• 金额: $ 29.71万
• 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 2010-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7257893
• 关键词: Mechanism; EGF; Mediated; Reduction; NEC

DESCRIPTION (provided by applicant): Necrotizing enterocolitis (NEC) is a major cause of morbidity and mortality in premature infants but the cause is unknown and there are no effective treatments. Using the rat model of NEC, we reported that epidermal growth factor (EGF) markedly reduced the incidence and severity of NEC. The central goal of this proposal is to clarify the molecular mechanism(s) of EGF-mediated reduction of NEC. Accelerated intestinal apoptosis has been shown in patients with NEC, and EGF can protect cells from apoptosis. Our preliminary studies indicate that EGF treatment of NEC regulates pro-survival signaling molecules in the site of NEC injury. Specific Aim 1 will clarify which pro-survival pathways are regulated by EGF treatment of NEC by evaluating EGF treatment (a) on pro-survival and pro-apoptotic genes and proteins in the ileum of neonatal rats with NEC, (b) in waved-2 mice (aberrant EGF-R signaling under non-pathogenic circumstances), (c) in intestinal cell lines where crucial pro-survival and pro-apoptotic genes are over-expressed or blocked and (d) in neonatal rats given EGF-R signaling inhibitors. Recently, we have shown a crucial role of enterohepatic circulation in NEC pathogenesis. Our preliminary data indicate that administration of EGF to neonatal rats with NEC down-regulates luminal bile acid (BA) levels and regulates BA transporters, suggesting an important role of EGF in BA homeostasis. In Specific Aim 2, we will explore the mechanism by which EGF regulates BA transport in the intestine during NEC by evaluating EGF-mediated changes in (a) BA transport in neonatal rats with NEC, (b) IEC lines where essential components of BA transport are over-expressed or blocked, and (c) in waved-2 mice. Heparin-binding EGF-like growth factor (HB-EGF) is a member of the family of EGF-related peptides. Our preliminary results show that HB-EGF reduces the incidence of experimental NEC and enhances EGF-mediated reduction of NEC. Thus, HB-EGF with EGF may provide better protection against NEC through unique nonantagonistic mechanisms. Specific Aim 3 will examine the mechanisms of HB-EGF-mediated reduction of NEC by (a) identifying the optimal route and dose to reduce NEC in neonatal rats, (b) determining the optimal combination of EGF and HB-EGF to reduce NEC, and (c) utilizing an in vitro intestinal injury model to evaluate mechanisms of HB-EGF-mediated reduction of NEC. These studies will elucidate the mechanisms of EGF-mediated reduction of NEC, information that is essential to initiate use of EGF as a preventative or treatment modality for human NEC.

描述（由申请方提供）：坏死性小肠结肠炎（NEC）是早产儿发病和死亡的主要原因，但原因不明，也没有有效的治疗方法。采用大鼠NEC模型，我们报道了表皮生长因子（EGF）明显降低NEC的发生率和严重程度。该建议的中心目标是阐明EGF介导的NEC减少的分子机制。NEC患者的肠道细胞凋亡加速，EGF可以保护细胞免于凋亡。我们的初步研究表明，EGF治疗NEC可以调节NEC损伤部位的促生存信号分子。具体目标1将通过评价EGF治疗（a）NEC新生大鼠回肠中促存活和促凋亡基因和蛋白，（B）wave-2小鼠中EGF治疗来阐明哪些促存活途径受NEC EGF治疗的调节（在非致病性情况下的异常EGF-R信号传导），（c）在肠细胞系中，其中关键的促存活和促凋亡基因过表达或被阻断，以及（d）在给予EGF-R信号传导抑制剂的新生大鼠中。最近，我们发现肠肝循环在NEC的发病机制中起着至关重要的作用。我们的初步数据表明，管理EGF的新生大鼠NEC下调管腔胆汁酸（BA）的水平和调节BA转运，这表明了重要的作用，EGF在BA的稳态。在具体目标2中，我们将探讨机制，EGF调节BA运输在肠NEC期间通过评估EGF介导的变化（a）BA运输在新生大鼠NEC，（B）IEC线，其中BA运输的基本组成部分被过度表达或阻断，（c）在波浪-2小鼠。肝素结合EGF样生长因子（HB-EGF）是EGF相关肽家族的成员。我们的初步结果表明，HB-EGF降低了实验性NEC的发病率，并增强了EGF介导的NEC的减少。因此，HB-EGF与EGF可以通过独特的非拮抗机制提供更好的保护作用。具体目标3将通过（a）鉴定在新生大鼠中降低NEC的最佳途径和剂量，（B）确定降低NEC的EGF和HB-EGF的最佳组合，和（c）利用体外肠损伤模型来评估HB-EGF介导的NEC降低的机制，来检查HB-EGF介导的NEC降低的机制。这些研究将阐明EGF介导的NEC减少的机制，这些信息对于开始使用EGF作为人类NEC的预防或治疗方式至关重要。