Novel genetic and salivary glycan biomarkers for risk of NEC in ELBW infants.

ELBW 婴儿 NEC 风险的新型遗传和唾液聚糖生物标志物。

• 批准号: 7754688
• 负责人: ARDYTHE L MORROW
• 金额: $ 60.64万
• 依托单位: CINCINNATI CHILDRENS HOSP MED CTR
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-01-15 至 2013-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7754688
• 关键词: Address; Alabama; Algorithms; Antibiotic Therapy; Antibiotics; Antigens; Arts; Bacteria; Binding; Biological Markers; Biology; Cell surface; Cessation of life; Clinical Data; Collaborations; DNA; DNA Library; Data; Data Set; Development; Disease; Ecology; Emergency Situation; Enrollment; Epitopes; Extremely Low Birth Weight Infant; FUT2 gene; Feces; Fucose; Fucosyltransferase; Future; Gastrointestinal tract structure; Gene Expression; Generations; Genes; Genetic; Genetic Polymorphism; Genotype; Glycosyltransferase Gene; Growth; Incidence; Individual; Infant; Inflammation; Informatics; Information Systems; Intervention; Intervention Trial; Intestines; Investigation; Measurement; Measures; Mediating; Methods; Microarray Analysis; Modeling; Molecular; Monitor; National Institute of Child Health and Human Development; Necrotizing Enterocolitis; Neonatal; Neonatal Intensive Care Units; Ohio; Outcome; Pathogenesis; Pathologic; Pattern; Phenotype; Polysaccharides; Predictive Value; Premature Infant; Prevention; Process; Recording of previous events; Research; Resources; Risk; Role; Saliva; Salivary; Sampling; Scientific Advances and Accomplishments; Sialic Acids; Subgroup; Surface; Techniques; Testing; Time; Transferase; Transferase Gene; Translational Research; base; clinical practice; experience; gastrointestinal; glycosyltransferase; high risk; high risk infant; improved; microbial; microbiome; molecular phenotype; neonate; novel; novel strategies; predictive modeling; premature; prevent; prophylactic; public health relevance; receptor; response; salivary H-2; sialyl Lewis a; success; sugar; tool

DESCRIPTION (provided by applicant): Extremely low birth weight (ELBW, <1000 gram) infants experience the highest incidence and case fatality of NEC. Biomarkers to predict NEC are lacking, especially in ELBW infants. Exciting new data indicate that specific fucosylated and sialylated glycans may serve as powerful predictors of NEC: H-2 is a major glycan epitope produced by the fucosyltransferase encoded by the FUT2 ("secretor") gene. Sialyl Lewis a (sLe ) is a major glycan produced by the combined catalytic function of transferases encoded by the FUT3 and a2-3 sialyl transferase genes. Expression of these glycans on the surface of the intestinal tract can be evaluated indirectly through gene polymorphisms or through measurement of salivary glycans. Our preliminary data indicate that risk of NEC is 4-fold higher and risk of death in NEC cases is 9-fold higher in infants with low or absent salivary H-2 and high sLea glycan compared to other ELBW infants, and that risk of death with NEC varies 5-fold among ELBW infants in relation to their FUT2 ("secretor") genotype. Thus, we propose a unique study of 600 ELBW infants enrolled in NICUs in Cincinnati, OH and Birmingham, AL, to test the hypotheses that FUT2 genotype and salivary glycan epitopes are strong predictors of risk of NEC, that they also function as biomarkers of intestinal bacterial colonization, and that alone or in combination with other biomarkers, they greatly improve our ability to predict risk of NEC in ELBW infants. The specific aims of this proposal are to: 1) Test FUT2 genotype and salivary H-2 and sLe phenotypes as novel biomarkers of subsequent risk of NEC; 2) Examine the pattern of intestinal bacterial colonization in ELBW infants in relation to their glycan genotype and phenotype, antibiotic treatment history, and NEC outcome; and 3) Determine the predictive value of multivariate models that include multiple putative biomarkers for risk of NEC, including gene polymorphisms, salivary glycans, and measures of early inflammation. This study will collect DNA for genetic studies, serial saliva for molecular phenotyping of antigens by EIA, and stool for microbiome analysis. Intestinal bacteria will be quantified through real-time qPCR of 16sDNA, and the comprehensive microbiome will be quantified by microarray analysis of stool samples. Standardized clinical data will be available through the NICHD Neonatal Research Network (NRN) data system augmented by chart review. We anticipate that the results of this study will provide a rich dataset that clarifies the ontogeny of intestinal glycan expression- microbial ecology and its relation to NEC. This project has unique potential to guide translational research to test novel interventions. Further, glycan expression biomarkers could be developed into new tools for monitoring premature infants. Our proposal directly addresses several objectives of the RFA by finding new biomarkers; improving multivariate predictive models by including biomarkers of early inflammation; and advancing understanding of the intestinal ecology of preterm infants. PUBLIC HEALTH RELEVANCE: Beneficial early bacterial colonization of the intestinal tract is known to help prevent necrotizing enterocolitis (NEC). The process of colonization causes a change in amounts of fucose-containing and sialic acid- containing sugars in the gastrointestinal tract. This project will study 600 extremely low birthweight infants in Cincinnati and Birmingham to test the measurement of saliva and the genes that control the synthesis of these sugars as novel biomarkers of risk of NEC and indicators of intestinal colonization.

描述（由申请人提供）：极低的出生体重（ELBW，<1000克）婴儿的发病率最高和病例死亡。缺乏预测NEC的生物标志物，尤其是在ELBW婴儿中。令人兴奋的新数据表明，特定的岩藻糖基化和溶解的聚糖可以作为NEC的有力预测指标：H-2是由FUT2（“ socretor”）基因编码的岩藻糖基转移酶产生的主要聚糖表位。 Siallyl Lewis A（SLE）是由FUT3和A2-3 siALlyl转移酶基因编码的转移酶的联合催化功能产生的主要聚糖。这些聚糖在肠道表面的表达可以通过基因多态性或通过测量唾液聚糖来间接评估。我们的初步数据表明，与其他ELBW婴儿相比，NEC病例的NEC风险高4倍，NEC病例中NEC死亡的风险高9倍，而NEC死亡的风险则高9倍，而NEC死亡的风险在ELBW婴儿中与其fut2相关的ELBW婴儿中的5倍变化。因此，我们提出了一项独特的研究，对俄亥俄州辛辛那提市和阿拉巴马州伯明翰市NICU的600名ELBW婴儿进行了测试，即测试FUT2基因型和唾液聚糖表位的假设是NEC风险的强有力预测指标，这些预测是NEC的风险，它们也可以作为NOM的生物标记，并在近代人的生物标记中起作用，并在其他风险中均具有危险，并且他们的生物标记能力是其他危险的，并且它们均具有众多的危险性，并且是众所周知的众所周知，众所周知，众所周知，众所周知，众所周知，众所周知的一流构成构造的能力。在ELBW婴儿中。该提案的具体目的是：1）测试FUT2基因型和唾液H-2和SLE表型，作为随后NEC风险的新生物标志物； 2）检查ELBW婴儿肠道细菌定植的模式与它们的聚糖基因型和表型，抗生素治疗史和NEC结局有关； 3）确定包括多种假定生物标志物的NEC风险，包括基因多态性，唾液聚糖以及早期炎症的度量，包括多种推定的生物标志物的预测价值。这项研究将收集用于遗传研究的DNA，通过EIA对抗原进行分子表型的系列唾液，以及用于微生物组分析的粪便。肠道细菌将通过16sDNA的实时QPCR进行量化，并通过对粪便样品的微阵列分析来量化全面的微生物组。标准化的临床数据将通过图表审查增强的NICHD新生儿研究网络（NRN）数据系统获得。我们预计这项研究的结果将提供丰富的数据集，以阐明肠道聚糖表达的个体 - 微生物生态学及其与NEC的关系。该项目具有指导转化研究以测试新干预措施的独特潜力。此外，可以将聚糖表达生物标志物开发到用于监测早产婴儿的新工具中。我们的建议直接通过找到新的生物标志物来直接解决RFA的几个目标。通过包括早期炎症的生物标志物来改善多元预测模型；并促进对早产肠生态的理解。公共卫生相关性：已知肠道的有益的早期细菌定植可帮助预防坏死性小肠结肠炎（NEC）。定殖的过程导致胃肠道中含有纤维素的含糖酸和含有唾液酸的糖的变化。该项目将研究辛辛那提和伯明翰的600名极低的出生体重婴儿，以测量唾液的测量以及控制这些糖的合成为NEC风险的新生物标志物和肠结构指标的新生物标志物。