Functional RNA Modifications, Micronutrient Exposure, Developmental Disabilities

功能性 RNA 修饰、微量营养素暴露、发育障碍

• 批准号: 10414928
• 负责人: XIAOBIN WANG
• 金额: $ 38.66万
• 依托单位: VIRGINIA POLYTECHNIC INST AND ST UNIV
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-06 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10414928
• 关键词: ASD patient; Address; Adipocytes; Affect; Attention; Biological Process; Birth; Blood specimen; Boston; Cell Differentiation process; Child; Clinical; Cohort Studies; Country; Coupled; DNA Methylation; DNA biosynthesis; Data; Defect; Development; Developmental Disabilities; Drosophila genus; Environmental Exposure; Epidemic; FMR1; Family; Folic Acid; Folic Acid Deficiency; Fragile X Syndrome; Frequencies; Funding; Genes; Genomic Instability; Grain; Health; Human; Individual; Intake; Investigation; Laboratory Study; Link; Measures; Messenger RNA; Metabolism; Methodology; Methylation; Micronutrients; Modification; Molecular; Multivitamin; Mus; National Health and Nutrition Examination Survey; Outcome; Pattern; Phosphorylation; Plasma; Pregnancy; Pregnant Women; Prevalence; Protein Overexpression; Proteins; Public Health; RNA; RNA methylation; Reader; Risk; Role; Sampling; Site; Societies; Supplementation; Testing; Tissues; Transcript; Transcriptional Regulation; Translations; Umbilical Cord Blood; United States National Institutes of Health; Untranslated RNA; Variant; Vitamin A; Vitamin B Complex; autism spectrum disorder; base; bisulfite sequencing; case control; cohort; comorbidity; cost effectiveness; design; disorder risk; folic acid supplementation; fortification; frontal lobe; genome-wide; improved; in utero; insight; mouse model; nerve stem cell; novel; overexpression; peripheral blood; polysome profiling; postnatal development; prenatal; prospective; protein expression; public health relevance; stem cell proliferation; toxicant; trait; transcriptome

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.

标题：功能性 RNA 修饰、微量营养素暴露、发育 残疾 项目概要 该提案将结合实验小鼠模型与人类预期出生队列的优势 研究和跨学科专业知识来测试功能性 RNA 甲基化（与 DNA 甲基化）可能是母体叶酸状态与 儿童患自闭症谱系障碍 (ASD) 的风险。母亲叶酸状况在儿童自闭症谱系障碍风险中的作用已得到证实 受到极大关注并正在争论中。虽然许多研究表明母亲叶酸摄入量较高会产生有益影响 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担忧。在波士顿 出生队列 (BBC)、PI 小组表现出母体叶酸水平存在很大差异，包括叶酸不足 过量，这与 NHANES（美国全国代表性样本）的发现一致。呈“U”形 发现母亲补充多种维生素的频率与自闭症谱系障碍 (ASD) 风险之间存在相关性；这 基于测量的母亲血浆叶酸水平的研究结果进一步支持了这种关联。 此外，PI 小组的初步数据表明，母亲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： 目标 1 将确定叶酸相关 使用小鼠神经干细胞 (NSC) 改变 RNA 甲基化和 RNA/DNA 甲基化动力学。 RNA/DNA 甲基化谱将使用全转录组和全基因组亚硫酸氢盐确定 测序、蛋白质翻译将通过多核糖体分析确定，以及叶酸相关的改变 将表征 NSC 增殖和分化。子宫内叶酸暴露相关的 RNA/DNA 将使用小鼠模型来确定甲基化改变。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。产前叶酸状态的相互关系， RNA/DNA 甲基化和儿童 ASD 风险将通过整合个体临床特征来确定 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的话，将 提供关于环境暴露（此处以叶酸为例）如何参与的新见解 RNA 修饰和 RNA/DNA 甲基化动力学的功能活动，这反过来可能与 造成不良健康后果（此处以自闭症谱系障碍（ASD）为例）。开发的方法将会有所帮助 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。