Convergence of genetic and gestational immune mechanisms in CHD8-related ASD

 描述（由申请人提供）：遗传学研究表明，自闭症和自闭症谱系障碍（ASD）是由复杂的遗传易感性引起的，这种遗传易感性与非遗传因素一起改变大脑发育。常见的遗传变异可能占ASD风险的50%，其余原因归因于其他因素2，3。即使是渗透性的单基因突变也不足以导致所有携带这种改变的个体患上自闭症 很明显，非遗传或“环境”因素必须与遗传相互作用，以改变ASD的风险。在美国，ASD的诊断率为1/68，因此开发反映基因-环境相互作用的动物模型变得至关重要，这些相互作用有助于ASD的发展。与ASD最强的环境关联之一是妊娠早期的母体免疫事件9 -11。这些影响并不需要胎儿感染，母体炎症反应的简单激活与风险增加相关9。尽管有强有力的证据表明遗传和免疫因素都有助于ASD，但很少有报告证实特定的遗传改变与妊娠免疫事件相互作用，导致或加重ASD的严重程度。动物模型证实，先天性母体免疫事件的激活单独足以引起神经发育和行为的改变15。还已知免疫诱导的胎盘损伤14，16或胎盘功能的改变17有助于这些效应。一些ASD风险基因与胎盘形成有关，我们认为妊娠早期某些类型的疾病或免疫激活暴露将与遗传风险协同作用，危及胎盘和发育中的胎儿。在这里，我们提供的证据表明，ASD风险基因chromodomain解旋酶DNA结合8（CHD 8）机械收敛与免疫相关的机制在胎盘和发育中的大脑。在这项提案中，小鼠和人类多能干细胞的实验将确定环境和CHD 8相关的遗传风险是否协同作用，以更严重地影响ASD的神经发育和功能。

 DESCRIPTION (provided by applicant): Genetic studies indicate that Autism and Autism spectrum disorders (ASD) result from a complex genetic predisposition that acts with non-genetic factors to alter brain development. Common genetic variation may account for up to 50% of ASD risk with remaining causes attributed to other factors 2,3. Even penetrant single gene mutations are not alone sufficient to cause autism in all individuals who carry the alteration and it is clear that non-genetic or "environmental" factors must interact with genetics to modify risk of ASD. With diagnoses at 1 in 68 in the United States8, it has become vital to develop animal models that reflect gene-environment interactions that contribute to the development of ASDs. One of the strongest environmental associations with ASD is a maternal immune event during early pregnancy9-11. Infections of the fetus are not required for these effects and simple activation of a maternal inflammatory response is associated with increased risk9. Despite strong evidence that that both genetic and immune factors contribute to ASD, there are very few reports confirming that specific genetic alterations interact with a gestational immune events to cause or worsen the severity of ASD. Animal models confirm that activation of an innate maternal immune event is alone sufficient to cause alterations in neurodevelopment and behavior 15. It is also known that immune-induced placental damage14,16 or alterations in placental function 17 contribute to these effects. Some ASD risk genes are involved in placentation and we propose that certain types of illness or immune-activating exposures during early pregnancy will synergistically converge with genetic risk to endanger the placenta and developing fetus. Here we provide evidence that the ASD risk gene chromodomain helicase DNA binding 8 (CHD8) mechanistically converges with immune-related mechanisms in both the placenta and developing brain. In this proposal, experiments in mice and with human pluripotent stem cells will determine whether environmental and CHD8-related genetic risks synergize to more severely impact neurodevelopment and function in ASD.