Maternal inflammation during pregnancy and neurodevelopmental disorders

怀孕期间母体炎症和神经发育障碍

• 批准号: 10407590
• 负责人: LISA A CROEN
• 金额: $ 60.9万
• 依托单位: KAISER FOUNDATION RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-07-15 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10407590
• 关键词: Address; Affect; Animal Model; Archives; Biological; Biological Assay; Biological Markers; Birth; Blood specimen; C-reactive protein; California; Caring; Cerebral Palsy; Characteristics; Child; Clinical; Clinical Data; Collection; Communicable Diseases; Data; Development; Developmental Delay Disorders; Diagnosis; Disease; Disease Marker; Early Intervention; Early identification; Electronic Health Record; Environment; Environmental Exposure; Environmental Risk Factor; First Pregnancy Trimester; Funding; Future; Genes; Genetic; Gestational Diabetes; Health; Heritability; Human; Immune; Immunoglobulins; Immunologic Markers; Individual; Inflammation; Inflammatory; Language; Lead; Learning; Light; Link; Lipids; Maternal Health; Measures; Mediating; Medical; Metabolic; Metabolic Diseases; Morbidity - disease rate; Mothers; Neuraxis; Neurodevelopmental Disorder; Non-Insulin-Dependent Diabetes Mellitus; Nonverbal Communication; Outcome; Pattern; Phenotype; Pregnancy; Pregnant Women; Prevalence; Prevention strategy; Primary Prevention; Quality of life; Research; Risk; Risk Factors; Role; Second Pregnancy Trimester; System; Time; Translating; United States; adipokines; autism spectrum disorder; biomarker identification; chemokine; cohort; cytokine; disorder risk; epidemiology study; fetal; genetic analysis; genome-wide; glucose tolerance; improved; life time cost; maternal condition; metabolic profile; modifiable risk; motor impairment; neurodevelopment; neuropsychiatry; offspring; postnatal period; pregnancy disorder; prenatal; prenatal testing; prepregnancy obesity; prevent; programs; prospective; public health relevance; societal costs; stem; study population

ABSTRACT Neurodevelopmental disorders (NDD) are a group of disorders in which the development of the central nervous system is disturbed. Approximately one in six children in the United States is affected by NDD, and the lifetime cost of supporting one individual with NDD exceeds $2 million. Commonly known NDD include autism spectrum disorders (ASD), cerebral palsy (CP), and developmental delays (DD). The causes of NDD are largely unknown, and few modifiable risk factors have been identified. A growing body of evidence supports a critical role for both genetic and environmental factors, particularly during gestation and the early postnatal period. Common immune-mediated and metabolic conditions as well as levels of immune and metabolic biomarkers have been shown to be associated with NDD risk. Furthermore, the immune and metabolic systems influence each other, and are in turn genetically-influenced. Our central hypothesis is that maternal inflammation during pregnancy stemming from immune or metabolic dysregulation will adversely impact child neurodevelopment. Previous studies of gestational markers of NDD risk primarily focused on one specific NDD, measured immune biomarkers at only one point in pregnancy, and didn't take into account maternal genetics or environmental exposures. We seek to overcome the limitations of previous studies and extend earlier findings linking maternal immune and metabolic function during pregnancy with increased risk of NDD by leveraging the comprehensive data previously collected for the Kaiser Permanente Research Program on Genes Environment and Health (RPGEH) Pregnancy Cohort, which includes ~15,000 pregnant women with archived first and second trimester blood samples, comprehensive information on demographic characteristics, maternal clinical status before and during pregnancy, and child outcomes from electronic health records. We seek funds to perform immune and metabolic assays on first and second trimester blood samples from mothers who gave birth to children diagnosed with ASD (N=150), CP (N=60), DD (N=1500), or who have no NDD (N=1000) and generate genome-wide maternal SNP data to support analyses addressing the following aims: 1) Characterize the maternal immune and metabolic profiles over pregnancy and evaluate whether there are specific longitudinal patterns that are associated with neurodevelopmental outcomes in the offspring, and 2) Identify maternal factors (demographic and clinical characteristics, genetics) that are associated with altered maternal immune or metabolic function during pregnancy and risk of different neurodevelopmental outcomes. Our study has the potential to identify immune and metabolic profiles during pregnancy that indicate risk for specific NDD. This would support the development of prenatal screening for NDD, leading to earlier intervention and the potential for preventing future morbidity and improving quality of life. Furthermore, the identification of prenatal biomarkers will illuminate the biologic mechanisms underlying aberrant neurodevelopment and provide an opportunity for developing preventive strategies.

摘要 神经发育障碍(NDD)是一组中枢神经发育障碍 系统受到干扰。在美国，大约六分之一的儿童受到新城疫的影响， 支持一个患有新城疫的人的成本超过200万美元。常见的NDD包括自闭症 谱系障碍(ASD)、脑性瘫痪(CP)和发育迟缓(DD)。引起新城疫的原因有 很大程度上是未知的，几乎没有可修改的风险因素被确定。越来越多的证据支持 遗传和环境因素的关键作用，特别是在孕期和出生后早期 句号。常见的免疫调节和代谢状况以及免疫和代谢水平 生物标记物已被证明与新城疫风险有关。此外，免疫和新陈代谢 各种系统相互影响，进而受到基因的影响。我们的中心假设是母体 由免疫或代谢失调引起的妊娠期炎症将对孩子产生不利影响 神经发育。以前对NDD风险的妊娠标志物的研究主要集中在一种特定的 NDD，只在怀孕期间的一个时间点测量免疫生物标记物，没有考虑母亲 遗传或环境暴露。我们试图克服以前研究的局限性，并扩展 早期发现孕期母体免疫和代谢功能与新城疫风险增加有关 通过利用之前为Kaiser Permanente研究计划收集的全面数据 基因环境与健康(RPGEH)妊娠队列，包括约15,000名患有 存档的妊娠早期和中期血液样本，关于人口统计特征的全面信息， 孕妇在怀孕前和怀孕期间的临床状况，以及电子健康记录中的儿童结局。我们 寻求资金，对来自中国的妊娠早期和中期血液样本进行免疫和代谢分析 生下被诊断为ASD(N=150)、CP(N=60)、DD(N=1500)的孩子的母亲或没有 NDD(N=1000)，并生成全基因组范围的母体SNP数据，以支持解决以下问题的分析 目的：1)描述孕妇在怀孕期间的免疫和代谢特征，并评估是否有 是特定的纵向模式，与后代的神经发育结果有关，以及 2)确定与改变有关的母体因素(人口统计和临床特征、遗传学) 孕妇在怀孕期间的免疫或代谢功能和不同神经发育结果的风险。 我们的研究有可能确定怀孕期间的免疫和代谢情况，这些情况表明有可能发生 特定新城疫。这将支持新城疫产前筛查的发展，导致更早 干预措施以及预防未来发病率和改善生活质量的潜力。此外， 产前生物标志物的鉴定将阐明异常的生物学机制 并为制定预防策略提供了机会。