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：
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
项目类别：
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

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.

项目概要/摘要坏死性小肠结肠炎 (NEC) 是一种毁灭性的早产儿并发症，突然发生并伴有发病率高，死亡率高，但尚无生物标志物。 NEC的高死亡率如果有一种可以早期发现疾病的筛查方法，那么这种情况就有可能得到预防。预测和 NEC 的预后工具对于推进我们的生物学洞察力以实现非侵入性治疗至关重要检测和准确及时的表型分析。我们开发了一个 NEC 生物储存库，其中包含各种样本类型和广泛的临床元数据前瞻性地从早产儿获得 NEC的发展。这些样本使我们能够探究 NEC 开发背后的机制，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道发育的方面。重要的是，表观遗传机制，特别是在新生儿 NEC 期间发生的 DNA 甲基化水平尚不清楚。我们初步的表观基因组数据表明，NEC 期间许多生物途径发生了改变。基于这些发现，我们现在假设甲基化特征的非侵入性识别可以识别有坏死风险的婴儿小肠结肠炎。我们将通过定义和量化粪便中的 DNA 甲基化特征来检验这一假设。 NEC 发生之前、期间和之后早产儿的血液。此外，我们还将扩大我们的观察发现多个关键途径的失调是 NEC 的一个明确的致病特征，并使用我们的小鼠模型以获得 NEC 病理学的更多机制见解。根据该提案的结论，我们将在整个时间过程中从婴儿身上生成大量基因组数据 NEC 的发生和表现，以及早产儿正常宫外发育过程中。这些研究将增进我们对 NEC 过程中所涉及途径的表观基因组调控的理解此外，还可以解释早产儿对 NEC 的独特易感性，并确定诊断这种毁灭性疾病的非侵入性方法。