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: 7932476
• 负责人: ARDYTHE L MORROW
• 金额: $ 5.99万
• 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: 2009-09-30 至 2011-09-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7932476
• 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）婴儿的 NEC 发病率和病死率最高。缺乏预测 NEC 的生物标志物，尤其是 ELBW 婴儿。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 的强大预测因子：H-2 是由 FUT2（“分泌者”）基因编码的岩藻糖基转移酶产生的主要聚糖表位。 Sialyl Lewis a (sLe ) 是一种主要聚糖，由 FUT3 和 a2-3 唾液酸转移酶基因编码的转移酶的联合催化功能产生。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，唾液 H-2 含量低或缺失且 sLea 聚糖含量高的婴儿发生 NEC 的风险高出 4 倍，死亡风险高出 9 倍。 ELBW 婴儿的 NEC 与其 FUT2（“分泌者”）基因型相关，差异为 5 倍。因此，我们提出了一项独特的研究，对俄亥俄州辛辛那提和阿拉巴马州伯明翰的新生儿重症监护室登记的 600 名 ELBW 婴儿进行了一项独特的研究，以检验以下假设：FUT2 基因型和唾液聚糖表位是 NEC 风险的强预测因素，并且它们也可作为肠道生物标志物细菌定植，单独或与其他生物标志物结合，它们极大地提高了我们预测 ELBW 婴儿 NEC 风险的能力。该提案的具体目标是： 1) 测试 FUT2 基因型以及唾液 H-2 和 sLe 表型作为后续 NEC 风险的新型生物标志物； 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 结果的关系； 3) 确定多变量模型的预测价值，该模型包括多种 NEC 风险的假定生物标志物，包括基因多态性、唾液聚糖和早期炎症指标。这项研究将收集 DNA 用于遗传学研究、连续唾液用于通过 EIA 对抗原进行分子表型分析，以及粪便用于微生物组分析。肠道细菌将通过 16sDNA 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丰富的数据集，阐明肠道聚糖表达的个体发育-微生物生态学及其与 NEC 的关系。该项目具有指导转化研究测试新颖干预措施的独特潜力。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 RFA 的几个目标；通过纳入早期炎症的生物标志物来改进多变量预测模型；并增进对早产儿肠道生态的了解。公众健康相关性：众所周知，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，以测试唾液测量和控制这些糖合成的基因，作为 NEC 风险的新型生物标志物和肠道定植指标。