Contribution of maternal immune activation, viral infection and epigenetics to autism--a community-based case control study

母体免疫激活、病毒感染和表观遗传学对自闭症的影响——基于社区的病例对照研究

• 批准号: 10658499
• 负责人: Carolyn M Salafia
• 金额: $ 52.99万
• 依托单位: INSTITUTE FOR BASIC RES IN DEV DISABIL
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-05-03 至 2028-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10658499
• 关键词: Acute; Affect; Amniotic Fluid; Apoptosis; Archives; Basal Plate; Biological Assay; Birth; Blood; Blood Vessels; Brain; Case/Control Studies; Cell physiology; Child; Childhood; Chronic; Clinic; Clinical; Communities; Community Healthcare; Complex; Computer Assisted; Computerized Medical Record; DNA Methylation; Data; Development; Diagnosis; Dryness; Early Intervention; Emotional; Environment; Epigenetic Process; Exposure to; Family; Female; Formalin; Functional disorder; Genes; Genetic; Genetic Risk; Genome; Goals; Growth; Growth Factor; Heredity; Histologic; Histopathology; Hospitals; Immune signaling; Immunophenotyping; Impairment; Infant; Infection; Inflammation; Inflammatory; Label; Language; Life; Link; Measures; Methodist Church; Methods; Methylation; Modeling; Modification; Neonatal; Neonatal Screening; Neurodevelopmental Disorder; Neuronal Dysfunction; New York; Newborn Infant; Organ; Paraffin Embedding; Pathogenesis; Pathology; Pathway interactions; Perinatal; Perinatal Infection; Placenta; Population; Pregnancy; Preparation; Presbyterian Church; Process; Reproducibility; Research; Resources; Risk; Sampling; Siblings; Site; Spottings; Stereotyped Behavior; Surface; Symptoms; Testing; Tissue Embedding; Tissues; Trees; United States; Villous; Virus Diseases; Work; autism spectrum disorder; case control; cell type; chemokine; cohort; cytokine; deep learning; disorder risk; economic cost; fetal; gene network; immune activation; improved; in utero; inflammatory marker; male; methylation pattern; neonatal brain; neonate; neurodevelopment; neutrophil; population based; prenatal; prenatal exposure; prenatal risk factor; screening; sex; social; time use; tissue archive; viral DNA

PROJECT SUMMARY/ABSTRACT Autism spectrum disorder (ASD) is a broad range of related neurodevelopmental disorders that are expressed within the first 2 to 3 years of life as stereotypic behaviors, and language and social-emotional impairments. ASD affects about 1 in 59 children in the United States and carries a high economic cost to families and communities. While there is a contribution of heredity, a growing body of research suggests that ASD has origins in utero. Specifically, evidence is accumulating that prenatal inflammation is a critical exposure in the causal pathway of at least a subset of ASD. Notably, this exposure may operate through sex-dimorphic effects on the placenta on fetal brain development, consistent with the high ASD risk for males relative to females. In our community-based hospital population, unique due to mandated universal placental histopathology assessment and linkage to pediatric community care, pilot analyses identified a 3-to-7-fold increased risk of childhood ASD associated with prenatal exposure to acute and/or chronic inflammation (AI, CI). This marker was seen in ~25% of low-risk children eventually diagnosed with ASD. These inflammatory placental pathologies were not marked by any maternal signs or symptoms during pregnancy. In addition, we identified a 13-fold increased odds of ASD risk with placental villous maldevelopment (PVM). We propose here to test pathways from these placental histopathology diagnoses to eventual ASD diagnosis. We will begin with targeted formalin-fixed paraffin-embedded (FFPE) placental histopathology of AI, CI, and PVM. We will then employ detailed and quantitative immunophenotyping of placental-decidual tissue at the placental-maternal interface. We can thoroughly profile cell type, cell function markers, and inflammation activation/apoptosis targets at the same time by using computer-assisted deep learning that allows precise tracking of immunolabeling and minimizes concerns of label overlap that can confound interpretation of immunofluorescent preparations. We will next assess newborn circulating levels of cytokines, chemokines, and growth factors, alterations of which are known to impact neurodevelopmental processes key to the genesis of neuronal dysfunction manifested in ASD. We will also examine epigenetic pathways by assessing DNA methylation in the placenta and its link to inflammation and PVM. Our analyses will test these as pathways from placental/decidual tissue markers of inflammation and/or PVM to ASD diagnosis. No other ASD case-control sample in a community-based population has universal access to FFPE tissue. This proposed project will open a unique window on the prenatal environment underlying ASD. Clarification of the pathways operating in community-based ASD will elucidate the mechanisms involved in ASD risk.

项目总结/摘要 自闭症谱系障碍（ASD）是一种广泛的相关神经发育障碍， 在生命的最初2到3年内，这些疾病表现为刻板行为、语言和社交情感障碍。 ASD影响美国约1/59的儿童，给家庭带来很高的经济成本， 社区.虽然有遗传的贡献，越来越多的研究表明，ASD 起源于子宫具体来说，越来越多的证据表明，产前炎症是一个关键的暴露在 ASD的至少一个子集的致病途径。值得注意的是，这种暴露可能通过性别二态效应起作用 胎盘对胎儿大脑发育的影响，与男性相对于女性的ASD高风险相一致。在 我们以社区为基础的医院人群，由于强制性的普遍胎盘组织病理学， 评估和联系儿科社区护理，试点分析确定了3至7倍的风险增加， 与产前暴露于急性和/或慢性炎症（AI，CI）相关的儿童ASD。该标记 在最终诊断为ASD的低风险儿童中，约有25%的人出现了这种情况。这些炎症性胎盘 在妊娠期间，病理学不以任何母体体征或症状为标志。此外，我们还发现了一个 13-ASD风险与胎盘绒毛发育不良（PVM）的几率增加一倍。 我们在此建议测试从这些胎盘组织病理学诊断到最终ASD的途径 诊断.我们将开始有针对性的福尔马林固定石蜡包埋（FFPE）胎盘组织病理学AI， CI和PVM。然后，我们将采用详细的和定量的免疫表型胎盘蜕膜组织， 胎盘与母体的界面我们可以彻底分析细胞类型、细胞功能标记和炎症 通过使用计算机辅助的深度学习，同时激活/凋亡靶点， 跟踪免疫标记，并最大限度地减少可能混淆免疫标记解释的标记重叠问题。 免疫荧光制剂。我们接下来将评估新生儿循环中细胞因子、趋化因子和 生长因子，已知其改变会影响神经发育过程， ASD表现为神经元功能障碍。我们还将通过评估DNA， 胎盘中的甲基化及其与炎症和PVM的联系。我们的分析将测试这些途径 从炎症和/或PVM的胎盘/蜕膜组织标志物到ASD诊断。 在社区人群中，没有其他ASD病例对照样本可以普遍获得FFPE组织。 这个拟议的项目将打开一个独特的窗口产前环境的基础ASD。澄清 在以社区为基础的ASD中运作的途径将阐明ASD风险中涉及的机制。