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

母亲的逆境、炎症和神经发育：代际过程如何在资源匮乏的环境中延续劣势

• 批准号: 10356126
• 负责人: Cristiane S. Duarte
• 金额: $ 48.03万
• 依托单位: NEW YORK STATE PSYCHIATRIC INSTITUTE DBA RESEARCH FOUNDATION FOR MENTAL HYGIENE, INC
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-03-16 至 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10356126
• 关键词: Age; Attention deficit hyperactivity disorder; Behavior Control; Behavior assessment; Birth; Brain; Brazil; C-reactive protein; Child; Clinic; DNA; DNA Methylation; Data; Development; Diffusion; Disadvantaged; Disease; Enrollment; Epigenetic Process; Etiology; Exposure to; Family; Female; Functional Magnetic Resonance Imaging; Functional disorder; Funding; Future; Gene Expression; Gene Expression Regulation; Generations; Genes; Genetic; Genetic Risk; Genetic Transcription; Hair; Healthcare Systems; Home; Home environment; Hydrocortisone; Immune; Immunoassay; Impulsive Behavior; Impulsivity; Infant; Inflammation; Inflammatory; Insula of Reil; Interleukin-1 beta; Interleukin-6; International; Knowledge; Life; Magnetic Resonance Imaging; Measures; Mediating; Mental disorders; Meta-Analysis; Methylation; Modeling; Moods; Odds Ratio; Outcome; Pathway interactions; Patient Self-Report; Perinatal; Peripheral; Placenta; Prefrontal Cortex; Pregnancy; Pregnant Women; Prevention; Preventive; Primary Health Care; Process; Proxy; Recording of previous events; Research; Research Infrastructure; Research Personnel; Resource-limited setting; Rest; Risk; Role; Sexual abuse; Sexually Transmitted Diseases; Site; Stress; Substance Use Disorder; TNF gene; Techniques; Testing; Third Pregnancy Trimester; Time; Toddler; United States National Institutes of Health; Universities; Work; abuse neglect; adverse childhood events; base; brain behavior; childhood adversity; cognitive control; depressive symptoms; design; fetal; genome wide association study; high risk; high risk sexual behavior; indexing; inflammatory marker; intergenerational; male; mood symptom; neural circuit; neurodevelopment; neurodevelopmental effect; next generation; offspring; parental monitoring; perceived stress; polygenic risk score; poor communities; postnatal; pre-clinical; pre-clinical research; prenatal; prenatal stress; response; sex; transcriptome sequencing; transmission process

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.

项目概要 不良童年经历（ACE）——包括身体/性虐待、忽视或父母的虐待 精神疾病——精神功能障碍的风险不仅存在于那些直接暴露的人身上，而且还导致 然而，这些 ACE 相关代际的潜在机制。 影响尚不清楚，极大地限制了独特的预防机会。 母体 ACE 影响后代神经发育的机制，特别关注 为此，我们将加入巴西全民医疗保健系统。 (SUS)，有 (n=290) 和没有 (n=290) 大量 ACE 病史的孕妇，并遵循 他们的后代在生命的头两年专注于认知控制的神经发育， 冲动行为的未来发展的基石 首先，我们将从测试开始。 使用婴儿 MRI 和 其次，我们将研究这些背后的机制。 协会，重点关注产前炎症和胎盘的作用，利用技术 检查 DNA 表观遗传学和 RNA 测序，同时也考虑遗传影响。 临床前研究表明，我们冒着产前炎症对男性的不同影响 此外，我们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 家庭内部评估揭示代际传播机制。 逆境中，我们的研究将为高影响力的预防性研究奠定基础。 圣保罗的基础设施 高风险、资源匮乏社区的初级保健诊所网络 R01 提案的目的是预防性效果能够发挥最大作用。 对 NIH-FAPESP 资助计划 (NOT-TW-16-001) 高度响应，该计划旨在支持 美国研究人员与美国著名研究小组之间的国际合作研究 巴西圣保罗州。