Novel Anti-Inflammatory Properties of Breast Milk in Necrotizing Enterocolitis

描述(由申请人提供)：本申请是K08职业发展奖，调查母乳在坏死性小肠结肠炎(NEC)中的新型抗炎特性。每10名体重不足1500克的早产儿中，就有近1人感染NEC，死亡率高达50%。其特点是肠屏障破坏、肠坏死、多系统器官衰竭和死亡。NEC发生的具体分子机制尚不清楚。我们的实验室已经证明，细菌脂多糖受体Toll样受体4(TLR4)的激活是NEC发生所必需的，TLR4的激活导致了NEC的两个关键病理特征：核因子-kB介导的炎性反应伴随着相关的肠道损伤和粘膜修复受损。母乳是唯一已知的对NEC的保护剂，但具体的保护成分和保护机制尚不清楚。我们的初步研究表明，母乳减少了TLR4信号，而介导这种保护作用的一个主要因素是表皮生长因子(EGF)。总的假设是，EGF受体的激活至少通过拮抗TLR4信号的两个主要有害方面来改善NEC：炎症和受损的上皮愈合。EGFR激活的保护作用可能涉及几个信号转导通路的竞争性相互作用。因此，我们进一步假设，母乳中的EGF通过增加Wnt和降低Notch的活性来促进肠道细胞的愈合。为了验证这一假说，我们将使用我们的实验性NEC模型来追求以下具体目标：1.确定母乳在多大程度上抑制TLR4介导的NEC炎症信号。2.研究母乳对小鼠肠上皮细胞增殖和粘膜愈合的影响。3.探讨在NEC发病机制中，母乳通过TLR4介导的Notch激活调节肠上皮细胞分化的机制。这位候选人是一名新生儿专家，在过去的四年里一直与她的导师密切合作。她得益于一位久负盛名的成功导师和支持性的学术环境。此外，候选人还定期会见她的科学咨询委员会，该委员会由免疫学、细胞生物学和生理学专家组成，她的合作者詹妮弗·格兰蒂斯博士在EGFR信号转导方面具有专业知识。这位候选人的近期目标是增加分子生物学、免疫学和信号转导方面的知识。她的长期职业目标是成为一名富有成效的独立研究员，将对NEC发病机制的研究领域做出重大贡献。为了实现这些目标，制定了一项有条理的职业发展计划，其中包括：通过教育活动、课程工作、会议获得知识，经常召开辅导员会议，逐步提高独立性，并设立一个致力于候选人成功的科学咨询委员会。

DESCRIPTION (provided by applicant): This application is for a K08 Career Development Award investigating the novel anti-inflammatory properties of breast milk in necrotizing enterocolitis (NEC). NEC affects nearly 1 out of 10 premature infants weighing less than 1500 grams, with a mortality of up to 50%. It is characterized by intestinal barrier disruption and intestinal necrosis, multi-system organ failure and death. The specific molecular mechanisms responsible for the development of NEC remain unclear. Our laboratory has shown that activation of the bacterial lipopolysaccharide receptor, toll-like receptor 4 (TLR4) is required fo NEC development and that TLR4 activation leads to two key pathological features of NEC: NF-kB-mediated inflammatory response with associated intestinal injury and impaired mucosal healing. Breast milk is the only known protective agent against NEC, but the specific protective component and protective mechanism remain unknown. Our preliminary studies show breast milk decreases TLR4 signaling and a major factor mediating this protective effect is epidermal growth factor (EGF). The overall hypothesis is that activation of the EGF receptor ameliorates NEC by antagonizing at least two major deleterious aspects of TLR4 signaling: inflammation and impaired epithelial healing. The protection seen with EGFR activation likely involves the competitive interaction of several signal transduction pathways. Therefore, we further hypothesize that the EGF in breast milk promotes intestinal cell healing by enhancing Wnt and decreasing Notch activation. To test this hypothesis, we will use our experimental NEC model to pursue the following specific aims: 1. To determine the extent that breast milk inhibits TLR4-mediated inflammatory signaling in NEC. 2. To characterize the effects of breast milk on intestinal epithelial cell proliferation and mucosal healing. 3. To determine the mechanisms by which breast milk regulates intestinal epithelial cell differentiation via TLR4-mediated Notch activation in NEC pathogenesis. The candidate is a Neonatologist who has been working closely with her mentor for the past four years. She benefits from a well-established and successful mentor with a supportive academic environment. In addition, the candidate meets on a regular basis with her Scientific Advisory Committee, which is comprised of experts in Immunology, Cell Biology and Physiology, and her collaborator, Dr. Jennifer Grandis with expertise in EGFR signal transduction. The candidate's immediate goals are to gain increased knowledge in molecular biology, immunology and signal transduction. Her long-term career goals are to become a productive independent investigator who will significantly contribute to the field studying the pathogenesis of NEC. To achieve these goals, a structured career development plan was developed which includes: gaining knowledge through educational activities, course work, conferences, frequent mentor meetings with a gradual increase in independence and a Scientific Advisory Committee who is devoted to the candidate's success.