Functional RNA Modifications, Micronutrient Exposure, Developmental Disabilities

标题：功能性RNA修饰，微量营养素暴露，膳食 残疾 项目摘要 该方案将联合收割机的优点结合到实验小鼠模型和人类前瞻性出生队列中 研究和跨学科的专业知识，以测试新的假设，功能性RNA甲基化（加上 DNA甲基化）可能是母体叶酸水平与 自闭症谱系障碍（ASD）的儿童风险。母亲叶酸水平在儿童ASD风险中的作用已经得到 引起了极大的关注，并在辩论中。虽然许多研究表明，母亲摄入更多的叶酸 针对自闭症，一些研究提出了对产前高叶酸摄入量的潜在危害的关注。在波士顿 出生队列（BBC），PI组显示了母亲叶酸水平的广泛变化，从不足 过量，这与美国全国代表性样本NHANES的发现一致。"U形" 发现母亲补充多种维生素的频率与ASD风险之间存在关系; 基于测量的母体血浆叶酸水平的结果进一步支持了这种关联。 此外，来自PI小组的初步数据表明，母体叶酸摄入量可能会影响 RNA甲基化代谢。提出了两个具体目标：Aim1将确定叶酸相关的 使用小鼠神经干细胞（NSC）的RNA甲基化和RNA/DNA甲基化动力学的改变。 将使用全转录组和全基因组亚硫酸氢盐测定RNA/DNA甲基化谱 测序，蛋白质翻译将使用多核糖体分析和叶酸相关的改变来确定， 将表征NSC增殖和分化。宫内叶酸代谢相关RNA/DNA 将使用小鼠模型测定甲基化改变。目标2将确定RNA甲基化位点 与脐带血样本中子宫内叶酸暴露有关。产前叶酸水平的相互关系， RNA/DNA甲基化和ASD儿童风险将通过整合个体临床特征来确定 与相应的RNA甲基化和DNA甲基化信息。这项研究如果成功，将 提供了关于环境暴露（这里以叶酸为例）如何参与 RNA修饰和RNA/DNA甲基化动力学的功能活动，这反过来可能与 有不良的健康结果（这里ASD被用作一个例子）。所制定的方法将有所帮助 研究其他微量营养素或有毒物质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.