Project 3: Immune Environment Interaction and Neurodevelopment

虽然自闭症谱系障碍（ASD）主要影响大脑功能，但我们的数据也发现了自闭症儿童（Au）免疫系统在系统和细胞水平上的广泛变化。免疫系统和神经系统之间的关系及其与环境暴露的协同作用的表征是理解毒物通过其改变神经发育的机制的关键。Ca ~（2+）依赖性信号传导，例如通过mTOR途径，提供了神经系统和免疫系统共同的分母。我们的数据收敛于特定的神经和免疫调节作用，牵连mTOR途径，离体暴露的细胞多溴联苯醚（多溴联苯醚）的同系物。项目3假设，母体妊娠期体内非共面环境毒物（如多溴二苯醚）的负荷与免疫失调有关。此外，我们假设患有Au的儿童对多溴联苯醚暴露的敏感性增加。我们认为，PBDE体内负荷的增加将导致细胞因子/趋化因子谱的变化 在妊娠期间从产下ASD儿童的母亲收集的外周血单核细胞的生产和离体毒物暴露将被夸大。我们进一步提出，ASD儿童对离体暴露于PBDE的敏感性增加，导致免疫细胞功能的差异改变，这与特定mTOR通路相关基因的表达改变相关。特别地，我们假设mTOR信号传导的改变将影响免疫应答的调节，包括调节性T细胞中表达的F0 XP 3的DNA甲基化的变化（项目2）。结合项目4，我们提出细胞因子/趋化因子谱和神经元发育的变化之间有直接的关系。我们已经制定了这些假设的基础上，我们发表的工作和初步数据表明，PMBC从ASD儿童的反应差异，离体多溴联苯醚暴露。我们将：1）通过利用从参加MARBLES（婴儿自闭症风险标志物-学习）的母亲在每个三个月期间采集的样本，检查母亲的妊娠环境。 早期迹象）研究; 2）通过使用在每个三个月期间从参加MARBLES研究的母亲采集的样品来检查母体妊娠环境;以及 从暴露于多溴联苯醚的外周血单核细胞（CHARGE）的现有样本中提取DNA，以确定甲基化差异是否反映了细胞功能的差异，包括细胞因子/趋化因子的产生。

Although autism spectrum disorder (ASD) primarily affects brain function, our data have also identified widespread changes in the immune system of children with autism (AU), both at the systemic and cellular levels. Characterization of the relationship between the immune and neuronal systems and their synergy with respect to environmental exposure is key to understanding the mechanisms through which toxicants can alter neurodevelopment. Ca^* dependent signaling, for example through the mTOR pathway, provides a denominator that is common to both the neural and immune systems. Our data converges on specific neuro and immune-modulatory effects, implicating mTOR pathways, following ex vivo exposure of cells to congeners of PBDE (polybrominated diphenyl ethers). Project 3 hypothesizes that the maternal gestational body burden of non-coplanar environmental toxicants such as PBDE will correlate to immune dysregulation. Furthermore, we hypothesize that children with AU will exhibit increased sensitivity to PBDE exposure. We propose that increased PBDE body burden will lead to changes in the profiles of cytokines/chemokines production and that ex vivo toxicant exposure of peripheral blood mononuclear cells collected during gestation from mothers who give birth to an ASD child will be exaggerated. We further propose that children with ASD will have increased sensitivity to ex vivo exposure to PBDE leading to differentially altered immune cell function that will correlate with the altered expression of specific mTOR pathway related genes. In particular, we hypothesize that alterations in mTOR signaling will affect regulation of immune responses including changes in DNA methlyation of F0XP3 expressed in regulatory T cells (Project 2). In conjunction with Project 4, we propose that there is a direct relationship between cytokine/chemokine profiles and changes in neuronal development. We have formulated these hypotheses on the basis of our published work and preliminary data demonstrating that PMBC from children with ASD respond differentially to ex vivo PBDE exposure. We will: 1) Examine the maternal gestational environment by leveraging samples taken during each trimester from mothers enrolled in the MARBLES (Markers of Autism Risk in Babies - Learning Early Signs) Study; 2) Examine the maternal gestational environment by using samples taken during each trimester from mothers enrolled in the MARBLES Study; and 3) Determine F0XP3 and global methylation on DNA from existing samples of PBDE-exposed peripheral blood mononuclear cells (CHARGE) to determine if methylation differences are reflective of differential cell function including cytokine/chemokine production.