Novel Anti-Inflammatory Properties of Breast Milk in Necrotizing Enterocolitis

描述（由申请人提供）：本申请是为了获得K08职业发展奖，研究母乳在坏死性小肠结肠炎（NEC）中的新型抗炎特性。每10个体重低于1500克的早产儿中就有1个患有NEC，死亡率高达50%。它的特点是肠屏障破坏和肠坏死，多系统器官衰竭和死亡。导致NEC发展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发展所必需的，TLR4的激活导致NEC的两个关键病理特征：nf - kb介导的炎症反应与相关的肠道损伤和粘膜愈合受损。母乳是唯一已知的针对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，母乳会降低TLR4信号，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受体的激活通过拮抗TLR4信号的至少两个主要有害方面来改善NEC：炎症和上皮愈合受损。EGFR激活的保护作用可能涉及几种信号转导途径的竞争性相互作用。因此，我们进一步假设母乳中的EGF通过增强Wnt和降低Notch激活来促进肠细胞愈合。为了验证这一假设，我们将使用我们的实验性NEC模型来追求以下具体目标：确定母乳对NEC中tlr4介导的炎症信号的抑制程度。2. 探讨母乳对肠上皮细胞增殖和粘膜愈合的影响。3. 探讨母乳在NEC发病过程中通过tlr4介导的Notch激活调控肠上皮细胞分化的机制。候选人是一名新生儿科医生，过去四年来一直与她的导师密切合作。她受益于一个成熟而成功的导师和一个支持性的学术环境。此外，候选人与她的科学咨询委员会定期会面，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Jennifer Grandis博士具有EGFR信号转导方面的专业知识。候选人的直接目标是在分子生物学，免疫学和信号转导方面获得更多的知识。她的长期职业目标是成为一名富有成效的独立研究者，为研究NEC的发病机制做出重大贡献。为了实现这些目标，我们制定了一个结构化的职业发展计划，其中包括：通过教育活动、课程作业、会议、频繁的导师会议来获得知识，并逐渐提高独立性，以及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.