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: 7531611
• 负责人: ARDYTHE L MORROW
• 金额: $ 68.72万
• 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/7531611
• 关键词: Address; Alabama; Algorithms; Antibiotic Therapy; Antibiotics; Antigens; Arts; Bacteria; Binding; Biological Markers; Biology; Cell surface; Cessation of life; Classification; 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）：极低出生体重（ELBW，<1000克）婴儿NEC的发病率和病死率最高。缺乏预测NEC的生物标志物，特别是在ELBW婴儿中。令人兴奋的新数据表明，特定的岩藻糖基化和唾液酸化聚糖可以作为NEC的有力预测因子：H-2是由FUT 2（“分泌”）基因编码的岩藻糖基转移酶产生的主要聚糖表位。唾液酸刘易斯a（sLe）是由FUT 3和α 2 -3唾液酸转移酶基因编码的转移酶的组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，低或缺乏唾液H-2和高sLea聚糖的婴儿NEC的风险高4倍，NEC病例的死亡风险高9倍，并且与FUT 2（“分泌者”）基因型相关的ELBW婴儿NEC死亡风险变化5倍。因此，我们提出了一项独特的研究，600 ELBW婴儿登记在NICU在辛辛那提，OH和伯明翰，AL，测试的假设，FUT 2基因型和唾液聚糖表位是NEC的风险强有力的预测因子，他们也作为肠道细菌定植的生物标志物，和单独或与其他生物标志物相结合，他们大大提高了我们的能力，预测NEC的风险ELBW婴儿。本提案的具体目的是：1）测试FUT 2基因型和唾液H-2和sLe表型作为NEC后续风险的新生物标志物; 2）检查ELBW婴儿肠道细菌定植模式与其聚糖基因型和表型、抗生素治疗史和NEC结局的关系;和3）确定多变量模型的预测值，所述多变量模型包括NEC风险的多种推定生物标志物，包括基因多态性、唾液聚糖和早期炎症的测量。本研究将收集DNA用于遗传研究，收集系列唾液用于EIA抗原的分子表型分析，收集粪便用于微生物组分析。肠道细菌将通过16 sDNA的实时qPCR进行定量，综合微生物组将通过粪便样本的微阵列分析进行定量。标准化的临床数据将通过NICHD新生儿研究网络（NRN）数据系统提供，并通过图表审查进行增强。我们预计，这项研究的结果将提供一个丰富的数据集，阐明肠道聚糖表达的个体发生-微生物生态学及其与NEC的关系。该项目具有独特的潜力，指导转化研究，以测试新的干预措施。此外，聚糖表达生物标志物可以开发成监测早产儿的新工具。我们的提案通过寻找新的生物标志物直接解决了RFA的几个目标;通过包括早期炎症的生物标志物来改善多变量预测模型;并促进对早产儿肠道生态学的理解。公共卫生相关性：已知有益的肠道早期细菌定植有助于预防坏死性小肠结肠炎（NEC）。定植过程导致胃肠道中含岩藻糖和含唾液酸的糖的量发生变化。该项目将研究辛辛那提和伯明翰的600名极低出生体重婴儿，以测试唾液和控制这些糖合成的基因的测量结果，作为NEC风险的新生物标志物和肠道定植的指标。