Placental Origins of Positive Child Health Outcomes

积极的儿童健康结果的胎盘起源

• 批准号: 10614112
• 负责人: Hudson Santos
• 金额: $ 1.01万
• 依托单位: UNIVERSITY OF MIAMI CORAL GABLES
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-04-08 至 2022-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10614112
• 关键词: Placental; Origins; Positive; Child; Health

PROJECT SUMMARY/ABSTRACT Despite numerous early life adversities, some children born extremely preterm (< 28 weeks’ gestation) remain free of adverse outcomes and have good quality of life. The biological mechanisms underlying protective pathways leading to positive health outcomes among extremely preterm children are not well-understood. However, we do know that placental biology plays a key role in determining child health. In this study, we will integrate multi-omics placental data, including gene expression, epigenetic regulators of gene expression (DNA methylation; microRNAs) and genotype to identify critical pathways linked to positive outcomes among children born extremely preterm. We will investigate an under-studied mechanism—functional changes in gene expression and placental multi-omics—as an early driver of positive health in children. This is the first study to explore placental multi-omics related to positive health. This proposal builds on our preliminary findings from the multi-center Extremely Low Gestational Age Newborns (ELGAN; n = 889) study, from which, (1) we published findings that 32% of ELGAN children exhibited no adverse health outcomes at age 10, and derived a positive child health index, strongly associated with quality of life scores; (2) we identified protective prenatal factors (e.g., higher maternal education) associated with positive child health that potentially effect biological pathways influencing health outcomes; and (3) we found that children with positive health at age 10 had reduced expression of inflammatory genes in the placenta compared with children with adverse outcomes (preliminary data). The central hypothesis of this proposed study is that reduced placental gene expression of inflammatory and stress-related pathways is associated with positive child health. We anticipate that these functional changes in gene expression are tied to microRNAs (miRNAs), DNA methylation and genotype. Our specific aims are to: 1) identify placental gene expression (mRNAs) changes associated with protective prenatal factors and positive child health outcomes at ages 10 and 15 years; and 2) determine regulators (e.g., DNA methylation) of gene expression associated with protective prenatal factors and positive child health at ages 10 and 15. This proposal builds on the existing data of the ELGAN study, which enrolled a cohort of children born < 28 weeks’ gestation, with follow-up rates of > 80%. From the ELGAN study (funded in the NIH Environmental influences on Child Health Outcomes (ECHO) program), we have access to: a) placental multi-omics data: gene expression (mRNAs), epigenetic transcriptional and post-transcriptional regulators of gene expression (miRNAs and DNA methylation, respectively), and gene sequences (genotype); b) child outcome at ages 10 and 15 years, robust measures of positive child health outcomes; c) prenatal and age 2 years factors: measures of prenatal factors and life adversities related to child health to use as covariates. This study is innovative because it will redirect research and public health efforts to identify biological pathways and antecedents of positive health amenable to laboratory testing and clinical trials to advance prediction and prevention of outcomes in at-risk children.

项目总结/摘要 尽管有许多早期生活的逆境，一些极早产儿（< 28周妊娠）仍然存在， 没有不良后果，生活质量良好。保护的生物学机制 导致极端早产儿积极健康结果的途径尚不清楚。 然而，我们确实知道胎盘生物学在决定儿童健康方面起着关键作用。在本研究中， 我们将 整合多组学胎盘数据，包括基因表达、基因表达（DNA）表观遗传调节因子 甲基化; microRNA）和基因型，以确定与儿童积极结果相关的关键途径 早产儿我们将研究一种尚未充分研究的机制--基因的功能变化 表达和胎盘多组学-作为儿童积极健康的早期驱动因素。这是第一次研究 探索与积极健康相关的胎盘多组学。 这项建议是根据我们从 多中心 极低胎龄新生儿（ELGAN; n = 889）研究，其中，（1） 我们发表 的发现 32%的ELGAN儿童在10岁时没有表现出不良的健康结果， 儿童健康指数，与生活质量评分密切相关;（2）我们确定了保护性产前因素（例如， 较高的母亲教育）与可能影响生物途径的积极儿童健康相关 影响健康结果;（3）我们发现，10岁时健康状况良好的儿童 胎盘中炎症基因的表达与不良结局儿童的比较（初步 数据）。这项研究的中心假设是，炎症因子的胎盘基因表达减少， 与压力相关的途径与积极的儿童健康有关。我们预计这些功能性变化 基因表达与microRNAs（miRNAs）、DNA甲基化和基因型有关。我们的具体目标是： 1)鉴定与保护性产前因素相关的胎盘基因表达（mRNAs）变化， 10岁和15岁的儿童健康结果;以及2）确定监管机构（例如，DNA甲基化） 与保护性产前因素和10岁和15岁儿童健康相关的表达。这项建议 建立在ELGAN研究的现有数据基础上，该研究招募了一组出生于妊娠< 28周的儿童， 随访率> 80%。来自ELGAN研究（由NIH环境对儿童的影响 健康结果（ECHO）计划），我们可以获得：a）胎盘多组学数据：基因表达 基因表达的表观遗传转录和转录后调节因子（miRNAs和DNA 甲基化）和基因序列（基因型）; B）10岁和15岁时的儿童结局，稳健 积极的儿童健康结果的措施; c）产前和2岁的因素：产前因素的措施 以及与儿童健康相关的生活逆境作为协变量。这项研究是创新的，因为它将重新引导 研究和公共卫生努力，以确定生物学途径和前因的积极健康适合 实验室检测和临床试验，以提高对高危儿童结局的预测和预防。