Bacterial Gastroenteritis Infection

母乳喂养对细菌性腹泻具有高度保护作用，细菌性腹泻是#年发病率和死亡率的主要原因。 孩子们。我们的总体目标是确定可以作为新的作用的分泌物人奶多糖 预防/治疗腹泻，尤其是细菌性腹泻的药物。我们认出了人类 乳寡糖，尤其是1，2-岩藻糖基(分泌物)低聚糖，能抑制一大类 病原体。分泌型寡糖与肠道病原体的粘附素结合，抑制其与细胞的结合 胃肠道表面的糖蛋白。我们还发现，母乳中的高分子量(HMW) 含有分泌物部分的糖蛋白与病原体结合很强，而且似乎具有更高的亲和力和 在抑制病原体方面比寡糖更具特异性。这个项目将研究结合 这些HMW人乳多糖的特性以确定它们的结构/功能关系，以及 找出那些疗效最高的人。这将允许理性地设计新一代人造人类 优化病原体结合抑制作用的牛奶多糖。该项目将继续生产2‘- 岩藻糖基乳糖(2‘-FL)是我们在我们的研究中心开发的合成分泌物人乳寡糖类似物 用于流产，并将在临床前研究中测试该产品的安全性和有效性。该项目将进一步 检查腹泻增加的负担！与非分泌型婴儿相比，分泌型婴儿的疾病 通过摄入母乳中的分泌物多聚糖来减轻疾病负担。因此，具体的 目的是：1)鉴定、分离和鉴定与细菌肠道结合的HMW分泌型糖蛋白 病原体，并确定糖基化模式对抑制强度的贡献。2) 在细菌中合成1，2-岩藻糖聚糖，并在动物模型中测试其安全性和有效性。3)测试 在0-2岁母乳喂养儿童队列中婴儿和母亲母乳的分泌物表型 婴儿所有腹泻和细菌性腹泻风险的决定因素。所获得的数据将扩展我们的 了解婴儿肠道和母乳中的多糖对新生儿的先天保护作用。这最终将是 转化为测试我们的原型合成人类乳葡聚糖作为一种新型的预防或治疗药物， 产生第二代合成多糖，以及一种新的预测糖尿病风险的生物标记物 拉肚子。 相关性(请参阅说明)： 这项申请中提出的研究旨在改变我们对人类的基本理解 牛奶多糖作为预防腹泻细菌致病风险的试剂，并将我们的发现转化为 促进婴儿健康和存活的新药物、食品物质和诊断工具 世界各地的儿童

Breastfeeding is highly protective against bacterial diarrhea, a major cause of morbidity and mortality in children. Our overallgoal is to identify secretor human milk glycans that can act as novel prophylactic/therapeutic agents against diarrhea, especially bacterial diarrhea. Weidentified human milk oligosaccharides, and especially a1,2-fucosyl (secretor) oligosaccharides, that inhibit a large family of pathogens. Secretor oligosaccharides bind to adhesins of enteropathogens, inhibiting their binding to cell surface glycans of the gastrointestinal tract. We also find that human milk high molecular weight (HMW) glycoproteins that contain secretor moieties bind strongly to pathogens, and seem to have higher affinity and more specificity in their inhibition of pathogens than oligosaccharides.This project will study binding characteristics of these HMW human milk glycans to determine their structure/function relationships, and dentify those with the highest efficacy. This will allow rational design of a new generation of synthetic human milk glycans that optimize inhibition of pathogen binding. This project will continue to produce 2'- fucosyllactose (2'-FL) the synthetic secretor human milk oligosaccharideanalog that we developed in our aboratory, and will test this product, in preclinical studies, for safety and efficacy. This project will further examine the increased burden of diarrhea! disease in secretor relative to non-secretor infants, and the reduced burden of disease obtained by consumption of secretor glycans in human milk. Thus, the specific aims are: 1) Identify, isolate and characterize HMW secretor glycoproteinsthat bind to bacterial enteric pathogens and determine the contributions of glycosylation patternsto the strength of inhibition. 2) Synthesize an a1,2-fucosylglycan in bacteria, and test its safety and efficacy in animal models. 3) Test the secretor phenotypes of infants and maternal milk in a cohort of breastfeeding children 0 - 2 years of age as determinants of infant risk of all diarrhea and bacterial diarrhea. The data obtained will extend our understanding of infant gut and human milk glycans in the innate defense of the neonate. This will ultimately translate into testing our prototype synthetic human milk glycan as a novel prophylactic or therapeutic agent, into generating a second generation synthetic glycan, as well as a novel biomarker for prediction of risk of diarrhea. RELEVANCE (See instructions): The research proposed in this application is designed to transform our fundamental understanding of human milk glycans as agents that prevent risk of bacterial causes of diarrhea and to translate our discoveries into new medications, food substances, and diagnostic tools that promote the health and survival of infants and children worldwide