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

基本信息

批准号：
10704229
负责人：
MISTY L GOOD
金额：
$ 58.99万
依托单位：
UNIV OF NORTH CAROLINA CHAPEL HILL
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-08-12 至 2025-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10704229
关键词：
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 DNA Methylation Inhibition Data Detection Development Diagnosis 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 Detection Onset of illness Operative Surgical Procedures Organ failure Pathogenesis Pathogenicity Pathologic Pathway interactions Phenotype Predisposition Premature Infant Premature Infant Diseases Regimen Regulation Reproducibility Resected Resources Risk Sampling Screening procedure Specimen Testing Time Uterus abdominal distension biobank bisulfite sequencing body system cell free DNA course development diagnostic strategy 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

项目摘要

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.

项目摘要/摘要坏死性小肠结肠炎（NEC）是早产的毁灭性并发症，突然发展并携带没有生物标志物的显着发病率和高死亡率。 NEC中看到的高死亡率如果有一种允许早期疾病检测的筛查方法，可能会预防。预测和 NEC的预后工具对于推进我们的生物学见解至关重要检测，准确及时的表型。我们已经开发了一个NEC生物座席标本类型和广泛的临床元数据是从早产婴儿中获得的 NEC的开发。这些样本使我们能够询问NEC开发的机制，包括遗传或环境因素。这些因素包括调节重要的表观遗传机制细胞分化和肠发展的各个方面。重要的是，特定于表观遗传机制新生儿NEC期间发生的DNA甲基化水平尚不清楚。我们的初步表观基因组数据表明，在NEC期间，许多生物学途径发生了改变。根据这些发现，我们现在假设非侵入性鉴定甲基化特征可以鉴定出有死灵风险的婴儿小肠结肠炎。我们将通过定义和量化粪便和 NEC发展前，期间和之后的早产婴儿的血液。此外，我们将扩大我们的观察到多个关键途径失调是NEC的定义致病特征，并使用我们小鼠模型以获得对NEC病理生物学的其他机械见解。根据提案的结论，在整个时间过程中，我们将从婴儿那里产生大量的基因组数据 NEC的发育和表现，以及早产儿正常发育期间。这些研究将促进我们对NEC期间涉及途径的表观基因组调节的理解开发以及此外，可以解释婴儿对NEC的独特敏感性并确定诊断这种毁灭性疾病的一种非侵入性方法。

项目成果

期刊论文数量（10）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Microfluidic Model of Necrotizing Enterocolitis Incorporating Human Neonatal Intestinal Enteroids and a Dysbiotic Microbiome.

结合人类新生儿肠肠类和失调微生物组的坏死性小肠结肠炎的微流体模型。

DOI：
10.3791/65605
发表时间：
2023
期刊：
Journal of visualized experiments : JoVE
影响因子：
0
作者：
Frazer,LaurenC;Yamaguchi,Yukihiro;Jania,CoreyM;Lanik,WyattE;Gong,Qingqing;Singh,DhirendraK;Mackay,Stephen;Akopyants,NataliaS;Good,Misty
通讯作者：
Good,Misty

Dilemmas in feeding infants with intestinal failure: a neonatologist's perspective.