Early environments, epigenetics, and inflammation during pregnancy

怀孕期间的早期环境、表观遗传学和炎症

• 批准号: 1440564
• 负责人: Thomas McDade
• 金额: $ 28.42万
• 依托单位: Northwestern University
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-01 至 2018-08-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1440564&HistoricalAwards=false
• 关键词: Early; environments; epigenetics; inflammation; during

Environments early in life, during critical periods of development, have lasting effects on human biology. It is well established that nutritional and microbial environments in infancy shape the development and function of the human immune system, but the long term effects of early environments on the regulation of inflammation are not known. Inflammation is important because acute inflammatory responses provide protection against infection, but chronic or dysregulated inflammatory responses contribute to diseases that represent major public health burdens in the US, including cardiovascular disease, diabetes, and adverse pregnancy outcomes like low birth weight and preterm delivery. Scientists also have discovered that epigenetic processes - chemical modifications to genes that have enduring effects on their activity - are important biological mechanisms through which adults 'remember' the environments they experienced early in life. By taking advantage of a unique longitudinal birth cohort study in the Philippines, with more than 30 years of prospective data, this project will contribute to scientific understandings of how environments in infancy can influence the regulation of inflammation in adulthood.The project focuses on pregnant women, since inflammation is activated as part of normal pregnancy, but dysregulated inflammation contributes to preterm labor and delivery and fetal growth restriction. The research tests the hypothesis that undernutrition in infancy (prenatally and postnatally), and low levels of exposure to common microbes (e.g., bacteria in soil, untreated water), contribute to elevated levels of inflammation during pregnancy. It also tests the hypothesis that elevated inflammation during pregnancy leads to adverse birth outcomes (preterm delivery, lower birth weight). Lastly, the project investigates methylation of inflammatory genes - an epigenetic process that modifies gene expression - as a biological mechanism linking early environments, inflammation, and birth outcomes. Data and samples come from an ongoing birth cohort study in the Philippines that has followed the same individuals since their mothers were pregnant with them in 1983-84. The dataset is unique in having the time depth, range of measures, and environmental variation necessary to test the project's hypotheses. Results will shed new light on the developmental processes that contribute to chronic inflammation, with potential implications for well-being of the next generation. In addition, the focus on epigenetics in relation to the social and physical contexts of development will encourage a reconceptualization of the human genome as a dynamic substrate that incorporates information from the environment to alter its structure and function.

生命早期的环境，在发展的关键时期，对人类生物学有持久的影响。众所周知，婴儿期的营养和微生物环境塑造了人类免疫系统的发育和功能，但早期环境对炎症调节的长期影响尚不清楚。炎症是重要的，因为急性炎症反应提供了对感染的保护，但慢性或失调的炎症反应有助于代表美国主要公共卫生负担的疾病，包括心血管疾病，糖尿病和不良妊娠结局，如低出生体重和早产。科学家们还发现，表观遗传过程-对基因的化学修饰对其活性产生持久影响-是重要的生物学机制，成年人通过这种机制“记住”他们在生命早期经历的环境。通过利用菲律宾独特的纵向出生队列研究，以及30多年的前瞻性数据，该项目将有助于科学地了解婴儿期环境如何影响成年期炎症的调节。该项目侧重于孕妇，因为炎症是正常妊娠的一部分，但失调的炎症导致早产和分娩以及胎儿生长受限。这项研究验证了婴儿期营养不良（产前和产后）和低水平接触常见微生物（例如，土壤中的细菌，未经处理的水），导致怀孕期间炎症水平升高。它还测试了怀孕期间炎症升高导致不良出生结果（早产，出生体重较低）的假设。最后，该项目研究了炎症基因的甲基化-一种改变基因表达的表观遗传过程-作为连接早期环境，炎症和出生结果的生物学机制。数据和样本来自菲律宾正在进行的一项出生队列研究，该研究自1983-84年母亲怀孕以来一直跟踪同一个人。该数据集在时间深度、测量范围和环境变化方面是独一无二的，这些都是测试项目假设所必需的。研究结果将揭示导致慢性炎症的发育过程，并对下一代的健康产生潜在影响。此外，注重与发展的社会和物质环境有关的表观遗传学，将鼓励重新认识人类基因组的概念，将其视为一个动态的基质，吸收来自环境的信息，改变其结构和功能。