Oligosaccharide moieties of human milk glycans that inhibit pathogens

抑制病原体的母乳聚糖的寡糖部分

基本信息

批准号：
8136058
负责人：
DAVID S. NEWBURG
金额：
$ 56.73万
依托单位：
BOSTON COLLEGE
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-09-23 至 2015-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8136058
关键词：
Accounting Antiviral Agents Artificial Feeding Binding Biological Assay Breast Feeding Carbohydrates Cell fusion Cell surface Cells Chondroitin Sulfates Complex Consumption Dairy Products Data Diarrhea Diet Discipline of Nursing Disease Engineering Enteral Genetic Engineering Glycoconjugates Glycolipids Glycoproteins Glycosaminoglycans Glycosphingolipids HIV HIV Envelope Protein gp120 HIV Infections Human Human Milk In Vitro Incidence Infant Infection Ingestion Inorganic Sulfates Intestines Kluyveromyces Leukocytes Lipid A Lipids Lymphocyte Mammary gland Milk Molecular Molecular Structure Molecular Weight Mothers Mucins Oligosaccharides Oral Phase Polysaccharides Proteins Public Health Relative (related person)Research Research Design Risk Rotavirus Rotavirus Infections Signal Transduction Solid Structure Sulfoglycosphingolipids Techniques Unspecified or Sulfate Ion Sulfates Vertebral column Virus Yeasts glycosylation glycosyltransferase macrophage pathogen receptor sugar

项目摘要

DESCRIPTION (provided by applicant): There is now strong data supporting our early hypothesis that the reduced incidence of enteric diseases in breastfeeding infants is due, in part, to protection by human milk glycans. Glycans, including glycoproteins, glycolipids, mucins, and glycosaminoglycans, contain complex oligosaccharide structures attached to proteins, lipids, and other molecular backbones. These complex carbohydrate moieties are synthesized by the many glycosyltransferases in the mammary gland; those glycans with homology to cell surface glycoconjugate pathogen receptors may inhibit pathogen binding, thereby protecting the nursing infant. Rotavirus and HIV infections in infants are introduced primarily through oral inoculation, and we discovered that these pathogenic viruses are strongly inhibited by specific high molecular weight human milk glycans in vitro. A subset of the human milk glycosaminoglycans, a chondroitin sulfate, and a component of the human milk sulfated glycosphingolipid fraction each strongly inhibit HIV in solid phase assays and in human leukocytes. A human milk glycoprotein, lactadherin (46 kDa), strongly inhibits rotavirus infection of MA 104 cells, and this molecule accounts for all of the inhibitory activity of human milk against rotaviruses in vitro. This proposal focuses on characterizing these actively antiviral glycans, using state-of-the-art instrumental analytical techniques that have recently become available and can provide detailed understanding of the molecular structure of complex glycan moieties. The molecular mechanisms will be studied to include the inhibition of multiple strains of the pathogens by the whole molecules. This will be followed by research to identify the smallest active moieties of the active molecules, and confirming their mechanism of pathogen inhibition. These studies are designed to culminate in a plan to synthesize the active moieties through genetic engineering of Kluyveromyces lactis, yeast occurring naturally in many dairy products of the human diet, and which has proved amenable to synthesis of other active human milk glycans. The availability of synthetic human milk glycans suitable for oral consumption that inhibit HIV or rotavirus could have large impact on these important threats to public health.

描述（由申请人提供）：现在有强有力的数据支持我们的早期假设，即母乳喂养婴儿肠道疾病发病率降低部分归因于母乳聚糖的保护。聚糖，包括糖蛋白、糖脂、粘蛋白和糖胺聚糖，含有附着在蛋白质、脂质和其他分子主链上的复杂寡糖结构。这些复杂的碳水化合物部分是由乳腺中的许多糖基转移酶合成的；那些与细胞表面糖缀合物病原体受体同源的聚糖可以抑制病原体结合，从而保护哺乳婴儿。婴儿轮状病毒和艾滋病毒感染主要通过口腔接种引入，我们发现这些病原病毒在体外受到特定高分子量母乳聚糖的强烈抑制。母乳糖胺聚糖的一个子集、硫酸软骨素和母乳硫酸化鞘糖脂部分的一个成分在固相测定和人类白细胞中均能强烈抑制 HIV。人乳糖蛋白乳粘素 (46 kDa) 强烈抑制 MA 104 细胞的轮状病毒感染，并且该分子解释了人乳在体外对轮状病毒的所有抑制活性。该提案的重点是使用最近可用的最先进的仪器分析技术来表征这些主动抗病毒聚糖，这些技术可以提供对复杂聚糖部分的分子结构的详细了解。将研究分子机制，包括整个分子对多种病原体菌株的抑制。随后将进行研究，以确定活性分子的最小活性部分，并确认其病原体抑制机制。这些研究旨在最终制定一项计划，通过乳酸克鲁维酵母的基因工程合成活性部分，乳酸克鲁维酵母是天然存在于人类饮食的许多乳制品中的酵母，并且已被证明适合合成其他活性母乳聚糖。适合口服食用、抑制艾滋病毒或轮状病毒的合成母乳聚糖的可用性可能会对这些对公共健康的重要威胁产生重大影响。