The Role of Human Milk in Infant Nutrition and Health

本竞争续约申请书由资深人士组成的多学科团队提交。 建议继续研究母乳中的生物活性因素的研究人员。我们的计划项目的独特之处在于它关注母乳以及母乳保护婴儿免受传染病侵袭的机制。本次更新的项目分别考虑了母乳在预防人类杯状病毒、轮状病毒、弯曲杆菌和相关疾病方面的作用。 病原菌；致病性肠出血性肠杆菌及相关病原菌；肠出血性肠杆菌稳定毒素。这个 项目协议利用体外分析、动物模型和人类受试者，并通过与涉及流行病学、生物统计学和转化研究的核心的互动来支持； 糖生物学和合成化学；以及分子生物学。在这份续期申请书中，我们 建议通过以下基本机制检查对多种病原体的保护 在母乳中表达的先天免疫和获得性免疫，特别是寡糖和相关的糖结合物，以及分泌性抗体。这一总体主题将通过研究这些母乳因子抑制病原体-细胞表面结合并提供针对多种病原体的交叉保护的程度来解决。我们还将研究母乳中低聚糖保护因子表达的变异性以及婴儿对腹泻疾病的易感性的遗传基础。根据当前赠款周期中进行的研究结果，这一更新将涉及在母乳中发现的低聚糖的合成，以及在临床前研究中测试其保护效果的转化研究，这些研究导致在幼儿中进行精心设计的第一阶段和第二阶段试验。

This application for competitive renewal is submitted by a multi-disciplinary team of senior investigators who propose to continue their studies on bioactive factors in human milk. Our program project is unique in its focus on human milk and the mechanisms by which human milk protects infants against infectious disease. The respective projects of this renewal consider the role of human milk in protection against human caliciviruses; rotavirus; campylobacter and related pathogens; enteropathogenic E. coil and related pathogens; and stable toxin (ST) of E. coil. The project protocols utilize in vitro assays, animal models, and human subjects, and are supported by interaction with cores that address epidemiology, biostatistics and translational research; glycobiology and synthetic chemistry; and molecular biology. In this application for renewal, we propose to examine protection against multiple pathogens through fundamental mechanisms of innate and adaptive immunity that are expressed in human milk, specifically, oligosaccharides and related glycoconjugates, and secretory antibody. This overall theme will be addressed by studying the extent to which these human milk factors inhibit pathogen-cell surface binding and provide cross-protection against multiple pathogens. We also will examine the genetic basis for variability in expression of oligosaccharide protective factors in human milk and infant susceptibility to diarrheal diseases. Based on results of studies conducted in the current grant cycle, this renewal will involve synthesis of oligosaccharides found in human milk and translational research that tests their protective efficacy in pre-clinical studies that lead to carefully designed phase I and II trials in young children.