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: 9917445
• 负责人: Cristiane S. Duarte
• 金额: $ 58.73万
• 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/9917445
• 关键词: Age; Attention deficit hyperactivity disorder; Behavior Control; Behavior assessment; Birth; Brain; Brazil; C-reactive protein; Child; Clinic; Communities; 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 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; Resources; Rest; Risk; Role; Sexual abuse; Sexually Transmitted Diseases; Site; Stress; Structure; 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; 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.

项目总结 不良童年经历(ACE)--包括身体/性虐待、忽视或父母 精神疾病--不仅直接接触者有精神功能障碍的风险，而且 下一代。然而，这些与ACE相关的代际机制 影响尚不清楚，这大大限制了一种独特的预防机会。我们的研究旨在检查 母体王牌影响子代神经发育的机制，特别关注 产前发炎。为此，我们将加入巴西全民保健系统 (SU)，有(290)和无(290)ACEs及以下病史的孕妇 他们的后代在出生后的头两年专注于认知控制的神经发展， 是未来冲动行为发展的基石。首先，我们将从测试开始 应用婴儿磁共振和核磁共振技术研究母体ACEs与子代脑行为发育的关系 认知控制的行为评估。第二，我们将研究这些基础的机制 关联，重点是产前炎症和胎盘的作用，使用技术 检查DNA表观遗传学和RNA测序，同时也考虑遗传影响。AS 根据临床前研究的建议，我们假设男性产前炎症的不同影响 与女性怀孕的对比。此外，我们还将探讨可修改的产后因素及其影响 关于子女的神经发育，监测父母的抑郁/情绪症状，并进行两次 对家庭的家庭内部评估。揭示人类免疫缺陷病毒代际传递机制 逆境，我们的研究将为高影响力的预防性研究奠定基础。我们将建立研究机构 S在圣保罗的基础设施 高风险、低资源社区的初级保健诊所网络 预防效果最能产生实质性影响的地方。此R01提案旨在 高度响应NIH-FAPESP筹资倡议(NOT-TW-16-001)，该倡议旨在支持 美国研究人员与美国一个恒星研究小组之间的合作国际研究 巴西保罗州S。