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: 10393088
• 负责人: LISA A CROEN
• 金额: $ 15.44万
• 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 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10393088
• 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.

抽象的 神经发育障碍（NDD）是一组疾病，中枢神经的发展 系统受到干扰。美国大约六分之一的孩子受NDD的影响，一生 NDD支持一个人的成本超过200万美元。众所周知的NDD包括自闭症 频谱障碍（ASD），脑瘫（CP）和发育延迟（DD）。 NDD的原因是 在很大程度上未知，几乎没有发现可修改的危险因素。越来越多的证据支持 遗传和环境因素的关键作用，尤其是在妊娠和早期产后的关键作用 时期。常见的免疫介导和代谢条件以及免疫和代谢水平 已显示生物标志物与NDD风险有关。此外，免疫和代谢 系统相互影响，反过来又受到遗传影响。我们的中心假设是母亲 因免疫或代谢失调引起的怀孕期间的炎症会对儿童产生不利影响 神经发育。先前对NDD妊娠标记的研究主要集中于一个特定 NDD，仅在怀孕时仅一点点测量的免疫生物标志物，并且没有考虑到母亲 遗传学或环境暴露。我们试图克服先前研究的局限性并扩展 早期的发现将孕妇免疫和代谢功能与NDD的风险增加联系起来 通过利用先前为Kaiser Permanente研究计划收集的综合数据 基因环境与健康（RPGEH）怀孕队列，其中包括约15,000名孕妇 存档的第一和第二个孕期血液样本，有关人口特征的全面信息， 孕妇临床状况在怀孕之前和期间，以及电子健康记录的儿童结局。我们 寻求资金在第一和第二孕期进行免疫和代谢测定 生育被诊断为ASD（n = 150），CP（n = 60），DD（n = 1500）或没有的儿童的母亲 NDD（n = 1000）并生成全基因组母体SNP数据以支持解决以下分析的分析 目的：1）在怀孕期间表征母体免疫和代谢特征并评估是否在那里 是与后代中神经发育结果相关的特定纵向模式，并且 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） 孕妇的母体免疫或代谢功能以及不同神经发育结果的风险。 我们的研究有可能识别怀孕期间的免疫和代谢特征，表明有风险 特定的NDD。这将支持开发NDD的产前筛查，导致 干预以及预防未来发病率和改善生活质量的潜力。此外， 产前生物标志物的识别将阐明异常的生物学机制 神经发育，并为制定预防策略提供了机会。