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

项目摘要/摘要 自闭症谱系障碍(Asd)是一种广泛的相关神经发育障碍，表现为 在生命的头2至3年内，作为刻板印象的行为，以及语言和社会情感障碍。 在美国，大约每59名儿童中就有一名患有自闭症，给家庭和家庭带来了高昂的经济成本 社区。虽然遗传有一定的作用，但越来越多的研究表明，ASD 起源于子宫。具体地说，越来越多的证据表明，产前炎症是一种严重的暴露在 ASD的至少一个子集的因果路径。值得注意的是，这种暴露可能是通过性别二态效应进行的。 胎盘对胎儿大脑发育的影响，这与男性相对于女性的ASD风险较高一致。在……里面 我们以社区为基础的医院人口，由于强制的通用胎盘组织病理学而独一无二 评估和与儿科社区护理的联系，试点分析发现， 儿童ASD与产前暴露于急性和/或慢性炎症(AI，CI)有关。这个记号笔 在最终被诊断为ASD的低风险儿童中，约有25%出现这种情况。这些炎性胎盘 在怀孕期间，病理没有任何母亲的体征或症状。此外，我们还确定了一个 ASD合并胎盘绒毛发育不良(PVM)的风险增加13倍。 我们建议在这里测试从这些胎盘组织病理学诊断到最终的ASD的路径。 诊断。我们将从人工智能的福尔马林固定石蜡包埋(FFPE)胎盘组织病理学开始， CI和PVM。然后，我们将对胎盘-蜕膜组织进行详细和定量的免疫表型鉴定 胎盘-母体界面。我们可以彻底分析细胞类型、细胞功能标记物和炎症 通过使用计算机辅助的深度学习来同时激活/凋亡目标，从而实现精确的 跟踪免疫标记，并最大限度地减少可能混淆解释的标记重叠问题 免疫荧光制剂。接下来，我们将评估新生儿循环中细胞因子、趋化因子和 生长因子，已知其变化会影响神经发育过程，而神经发育过程是糖尿病发生的关键 ASD表现为神经元功能障碍。我们还将通过评估DNA来检查表观遗传途径 胎盘中甲基化及其与炎症和PVM的关系。我们的分析将把这些作为路径进行测试 从胎盘/蜕膜炎症和/或PVM的组织标志物到ASD的诊断。 在以社区为基础的人群中，没有其他ASD病例对照样本能够普遍获得FFPE组织。 这个拟议的项目将打开一扇独特的窗口，了解自闭症潜在的产前环境。澄清 以社区为基础的ASD中运行的通路将阐明ASD风险所涉及的机制。

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.