Bacterial Gastroenteritis Infection

细菌性胃肠炎感染

• 批准号: 8318085
• 负责人: GUILLERMO RUIZ-PALACIOS
• 金额: $ 13.96万
• 依托单位: CINCINNATI CHILDRENS HOSP MED CTR
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8318085
• 关键词: 2 year old; Affinity; Animal Model; Bacteria; Bacterial Adhesins; Bacterial Gastroenteritis; Binding; Biological Markers; Biomedical Engineering; Breast Feeding; Campylobacter; Cell surface; Characteristics; Child; Consumption; Data; Diagnostic; Diarrhea; Disease; Dose; Epitopes; Escherichia coli; Family; Food; Gastrointestinal tract structure; Generations; Glycoproteins; Goals; Health; Human Milk; Individual; Infant; Infant Health; Infection; Instruction; Laboratories; Lead; Measures; Milk; Molecular Weight; Morbidity - disease rate; Mothers; Oligosaccharides; Pattern; Peptides; Pharmaceutical Preparations; Phenotype; Polysaccharides; Prevention; Preventive; Relative (related person); Research; Risk; Role; Safety; Specificity; Structure-Activity Relationship; Testing; Therapeutic; Therapeutic Agents; Translating; Translational Research; Vertebral column; analog; base; burden of illness; cohort; design; disorder risk; enteric pathogen; glycosylation; infant nutrition; inhibitor/antagonist; mortality; neonate; novel; pathogen; pathogenic bacteria; preclinical study; prevent; prophylactic; protective efficacy; prototype; public health priorities; tool; translational study

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

母乳喂养对预防细菌性腹泻有很强的保护作用，细菌性腹泻是婴儿发病和死亡的主要原因。 孩子们。我们的总体目标是确定可以作为新的分泌母乳聚糖 腹泻、特别是细菌性腹泻的预防/治疗剂。我们确认了人类 乳寡糖，尤其是 a1,2-岩藻糖基（分泌）寡糖，可抑制一大类 病原体。分泌寡糖与肠病原体的粘附素结合，抑制其与细胞的结合 胃肠道的表面聚糖。我们还发现母乳高分子量 (HMW) 含有分泌部分的糖蛋白与病原体牢固结合，并且似乎具有更高的亲和力和 与寡糖相比，它们对病原体的抑制更具特异性。该项目将研究结合 这些 HMW 母乳聚糖的特征以确定其结构/功能关系，以及 确定那些具有最高功效的人。这将使新一代合成人类的合理设计成为可能 乳聚糖可优化对病原体结合的抑制。该项目将继续生产2'- 岩藻糖基乳糖 (2'-FL) 是我们在我们的实验室中开发的合成分泌母乳寡糖类似物 实验室，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 检查腹泻负担增加！相对于非分泌者婴儿的分泌者疾病，以及 减少因食用人乳中的分泌聚糖而造成的疾病负担。因此，具体 目标是：1) 鉴定、分离和表征与细菌肠道结合的 HMW 分泌糖蛋白 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 a1,2-岩藻糖基聚糖，并在动物模型中测试其安全性和有效性。 3）测试 0-2岁母乳喂养儿童队列中婴儿和母乳的分泌表型 婴儿所有腹泻和细菌性腹泻风险的决定因素。获得的数据将扩展我们的 了解婴儿肠道和母乳聚糖在新生儿先天防御中的作用。这最终将 转化为测试我们的原型合成母乳聚糖作为新型预防或治疗剂， 生成第二代合成聚糖，以及用于预测风险的新型生物标志物 腹泻。 相关性（参见说明）： 本申请中提出的研究旨在改变我们对人类的基本理解 乳聚糖作为预防细菌性腹泻风险的药物，并将我们的发现转化为 促进婴儿健康和生存的新药物、食品物质和诊断工具 世界各地的儿童