Functional RNA Modifications, Micronutrient Exposure, Developmental Disabilities

标题：功能性RNA修饰，微量营养素暴露，发育 残障人士 项目总结 这项建议将结合实验小鼠模型和人类预期出生队列的优点。 研究和跨学科专业知识以测试新的假设，即功能性RNA甲基化(与 DNA甲基化)可能是母体叶酸状况和 儿童患自闭症谱系障碍(ASD)的风险。母亲叶酸状况在儿童患自闭症风险中的作用 引起了极大的关注，并正在辩论中。虽然许多研究表明，母亲摄入更高的叶酸有好处 针对自闭症，一些研究提出了对产前叶酸摄入量过高的潜在危害的担忧。在波士顿 出生队列(BBC)，Pi的小组表现出母亲叶酸水平的广泛差异，从不足到不足 这与美国全国代表性样本NHANES的研究结果一致。“U字形” 研究发现，母亲服用复合维生素的频率与患自闭症的风险有关；这 基于测量的母体血浆叶酸水平的研究结果进一步支持了这种联系。 此外，Pi小组的初步数据表明，母亲叶酸的摄入量可能会对 RNA甲基化代谢。提出了两个具体目标：AIM1将确定与叶酸相关的 使用小鼠神经干细胞(NSCs)的RNA甲基化和RNA/DNA甲基化动力学的变化。 RNA/DNA甲基化图谱将使用转录组范围和基因组范围的亚硫酸氢盐来确定 测序、蛋白质翻译将使用多聚体图谱以及与叶酸相关的改变来确定 将对神经干细胞的增殖和分化进行表征。宫内叶酸暴露相关的RNA/DNA 甲基化改变将使用小鼠模型来确定。AIM 2将确定RNA甲基化位点 与脐带血样本中的宫内叶酸暴露有关。胎儿期叶酸状况的相互关系 RNA/DNA甲基化和儿童患ASD的风险将通过结合个别临床特征来确定 具有相应的RNA甲基化和DNA甲基化信息。这项拟议的研究如果成功，将 提供有关环境暴露(此处以叶酸为例)如何参与 RNA修饰的功能活性和RNA/DNA甲基化动力学，这反过来可能是相关的 有不良的健康后果(这里以自闭症为例)。开发的方法论将是有帮助的 研究其他微量营养素或毒物对其他健康结果的分子基础。

TITLE: FUNCTIONAL RNA MODIFICATIONS, MICRONUTRIENT EXPOSURE, DEVELOPMENTAL DISABILITIES PROJECT SUMMARY This proposal will combine the strengths of experimental mouse model with human prospective birth cohort study and transdisciplinary expertise to test novel hypotheses that functional RNA methylation (coupled with DNA methylation) may be one of the mechanisms underlying the association between maternal folate status and child risk of autism spectrum disorders (ASD). The role of maternal folate status in child risk of ASD has received great attention and is in debate. While many studies suggest beneficial effect of higher maternal folate intake against autism, a few studies raised concern about the potential harm of high prenatal folate intake. In the Boston Birth Cohort (BBC), PI's group demonstrated a wide variation of maternal folate levels, ranging from insufficiency to excess, which is consistent with the finding in NHANES, a U.S. nationally representative sample. A `U shaped' relationship was found between frequency of maternal multivitamin supplementation and ASD risk; this association was further supported by the findings based on measured maternal plasma folate levels. Furthermore, the preliminary data from PI's group suggest that maternal folate intake may have an impact on RNA methylation metabolism. Two specific aims were proposed: Aim1 will determine folate-associated alterations in RNA methylation and RNA/DNA methylation dynamics using mouse neural stem cells (NSCs). RNA/DNA methylation profiles will be determined using transcriptome-wide and genome-wide bisulfite sequencing, protein translation will be determined using polysome profiling, and folate-associated alterations in NSC proliferation and differentiation will be characterized. In-utero folate exposure-associated RNA/DNA methylation alterations will be determined using a mouse model. Aim 2 will determine RNA methylation sites associated with in-utero folate exposure in cord blood samples. The inter-relationship of prenatal folate status, RNA/DNA methylation, and child risk of ASD will be determined via the integration of individual clinical features with corresponding RNA methylation and DNA methylation information. This proposed study, if successful, will provide new insight on how environmental exposures (here folate is used as an example) are involved in the functional activities of RNA modifications and RNA/DNA methylation dynamics, which in turn, may be associated with adverse health outcomes (here ASD is used as an example). The methodologies developed will be helpful to investigate molecular underpinnings of other micronutrients or toxicants on other health outcomes.