Non-invasive analysis of methylated cell free DNA in necrotizing enterocolitis

坏死性小肠结肠炎甲基化细胞游离 DNA 的无创分析

• 批准号: 10316733
• 负责人: MISTY L GOOD
• 金额: $ 68.7万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-12 至 2021-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10316733
• 关键词: Abdomen; Abdominal Radiography; Affect; Age of Onset; Air; Antibiotics; Biological; Biological Assay; Biological Markers; Biology; Blood; Blood specimen; Case-Control Studies; Cell Lineage; Chemicals; Clinical; Clinical Data; Complication; DNA; DNA Methylation; Data; Detection; Development; Diagnosis; Diagnostic; Diagnostic Procedure; Disease; Early Diagnosis; Economic Burden; Enterocytes; Environmental Risk Factor; Epigenetic Process; Excision; Feces; Gastrointestinal Diseases; Genetic; Genetic Transcription; Growth; Hematopoietic; Hypermethylation; Infant; Infection; Inflammatory Response; Intestines; Lasers; Leukocytes; Maps; Metadata; Methods; Methylation; Morbidity - disease rate; Necrosis; Necrotizing Enterocolitis; Neonatal; Non-Invasive Cancer Detection; Onset of illness; Operative Surgical Procedures; Organ failure; Pathogenesis; Pathogenicity; Pathologic; Pathway interactions; Phenotype; Predisposition; Premature Infant; Premature Infant Diseases; Regimen; Regulation; Resected; Resources; Risk; Sampling; Screening procedure; Specimen; Testing; Time; base; biobank; bisulfite sequencing; cell free DNA; course development; developmental disease; epigenome; epigenomics; feeding; genome-wide; genomic data; high risk; human tissue; improved; innovation; insight; intestinal injury; liquid biopsy; medication administration; microbiome; molecular phenotype; mortality; mouse model; neonatal mice; novel; novel marker; postnatal development; precision medicine; predictive tools; premature; prevent; prognostic tool; prospective; screening; single-cell RNA sequencing; stool sample; transcriptomics; whole genome

Project Summary/Abstract Necrotizing enterocolitis (NEC) is a devastating complication of prematurity that develops suddenly and carries significant morbidity and a high mortality rate for which no biomarkers exist. The high mortality rate seen in NEC could likely be prevented if there was a screening method that permitted early disease detection. Predictive and prognostic tools for NEC are essential to advance our biological insight with a view towards non-invasive detection and accurate and timely phenotyping. We have developed a NEC Biorepository with a variety of specimen types and extensive clinical metadata obtained prospectively from premature infants before the development of NEC. These samples allow us to interrogate the mechanisms that underlie NEC development, including genetic or environmental factors. These factors include epigenetic mechanisms that regulate important aspects of cellular differentiation and gut development. Importantly, the epigenetic mechanisms, specifically, at the level of DNA methylation that take place during neonatal NEC are unknown. Our preliminary epigenomic data demonstrate that numerous biological pathways are altered during NEC. Based on these findings, we now hypothesize that non-invasive identification of methylation signatures can identify an infant at risk for necrotizing enterocolitis. We will test this hypothesis by defining and quantifying the DNA methylation signatures in stool and blood of premature infants before, during and after the development of NEC. Moreover, we will expand on our observations that dysregulation of multiple key pathways is a defining pathogenic feature of NEC and use our mouse model to gain additional mechanistic insights into NEC pathobiology. By the conclusion of the proposal, we will have generated a considerable amount of genomic data from infants across the time course of development and manifestation of NEC, and also during the normal extrauterine development of preterm infants. These studies will advance our understanding of the epigenomic regulation of the pathways involved during NEC development, and furthermore, may explain the unique susceptibility of the premature infant to NEC and identify a non-invasive approach to diagnosing this devastating disease.

项目总结/文摘