Maternal adversity, inflammation, and neurodevelopment: How intergenerational processes perpetuate disadvantage in a low-resource setting

项目摘要 不良童年经历（ACE）-包括身体/性虐待，忽视或父母 精神疾病-不仅对直接接触者，而且对 下一代然而，这些与ACE相关的代际差异背后的机制 影响尚不清楚，严重限制了独特的预防机会。我们的研究旨在研究 母体ACE影响后代神经发育的机制，特别关注 产前炎症为此，我们将加入巴西全民保健系统， (SUS)，有（n=290）和无（n=290）大量ACE病史的孕妇，并随访 他们的后代在生命的头两年专注于认知控制的神经发育， 未来冲动行为发展的基石。首先，我们将从测试开始 使用婴儿MRI研究母体ACE与后代脑行为发育之间的关系， 认知控制的行为评估其次，我们将研究这些机制的基础 协会，重点是产前炎症和胎盘的作用，使用技术， 研究DNA表观遗传学和RNA测序，同时考虑遗传影响。作为 根据临床前研究的建议，我们假设男性产前炎症的影响不同 vs.女性怀孕此外，我们还将探讨可改变的产后因素及其影响 对后代神经发育的影响，监测父母的抑郁/情绪症状，并进行两次 家庭内部评估。揭示艾滋病毒的代际传递机制 我们的研究将为高影响力的预防性研究奠定基础。我们将建立研究 圣保罗的基础设施 高风险、低资源社区的初级保健诊所网络 在这些领域，预防效果可以发挥最大的作用。本R 01提案旨在 对NIH-FAPESP资助倡议（NOT-TW-16-001）反应积极，该倡议旨在支持 美国的研究人员和一个恒星研究小组之间的国际合作研究， 巴西圣保罗州。

PROJECT SUMMARY Adverse childhood experiences (ACEs) - which includes physical/sexual abuse, neglect or parental mental illness - confer risk for psychiatric dysfunction not only to those directly exposed, but also to the next generation. However, mechanisms underlying these ACE-related intergenerational effects are unclear, significantly limiting a unique prevention opportunity. Our study aims to examine mechanisms by which maternal ACEs influence offspring neurodevelopment, with special focus on prenatal inflammation. Toward this end, we will enroll, in the Brazilian Universal Health Care system (SUS), pregnant women with (n=290) and without (n=290) a history of substantial ACEs and follow their offspring over the first two years of life focused on the neurodevelopment of cognitive control, a cornerstone in the future development of impulsive behaviors. First, we will start by testing associations between maternal ACEs and offspring brain-behavior development using infant MRI and behavioral assessments of cognitive control. Second, we will examine mechanisms underlying these associations, focusing on the role of prenatal inflammation and the placenta using techniques to examine DNA epigenetics and RNA sequencing, while also taking into account genetic influences. As suggested by preclinical research, we hypothesize differential effects of prenatal inflammation in male vs. female pregnancies. In addition, we will explore modifiable post-natal factors and their influence on offspring neurodevelopment, monitoring parental depressive/mood symptoms and conducting two in-home assessments of the family. Revealing mechanisms of intergenerational transmission of adversity, our study will set the stage for high-impact preventive research. We will establish research infrastructure within a São Paulo primary care clinic network in a high-risk, low-resource community where preventive effects can have their most substantial impact. This R01 proposal is designed to be highly responsive to the NIH-FAPESP Funding Initiative (NOT-TW-16-001), which aims to support collaborative international research between investigators in the US and a stellar research group in the State of São Paulo, Brazil.