Functional RNA Modifications, Micronutrient Exposure, Developmental Disabilities

功能性 RNA 修饰、微量营养素暴露、发育障碍

基本信息

批准号：
10655495
负责人：
XIAOBIN WANG
金额：
$ 38.59万
依托单位：
VIRGINIA POLYTECHNIC INST AND ST UNIV
依托单位国家：
美国
项目类别：
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/10655495
关键词：
ASD patient Adipocytes Affect Anxiety Attention Biological Process Birth Blood specimen Boston Cell Differentiation process Child Clinical Cohort Studies Conceptions 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 Recommendation Risk Role Sampling Shapes Site Societies Supplementation Testing Tissues Transcript Transcriptional Regulation Translations Umbilical Cord Blood United States National Institutes of Health Untranslated RNA Variant Vitamin B Complex autism spectrum disorder bisulfite sequencing case control cohort comorbidity cost effectiveness demethylation 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

项目摘要

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，发育残疾项目摘要该建议将结合实验小鼠模型的优势与人类前瞻性出生队列研究和跨学科专业知识，以检验功能性RNA甲基化的新假设（与 DNA甲基化）可能是母体叶酸状况与自闭症谱系障碍的儿童风险（ASD）。母体叶酸状况在儿童ASD风险中的作用已收到非常关注，并在辩论中。虽然许多研究表明较高的母体叶酸摄入量有益反对自闭症，一些研究引起了人们对高产前叶酸摄入量的潜在危害的关注。在波士顿 PI的出生队列（BBC），表现出孕产妇叶酸水平的广泛变化，范围从不足过剩，这与美国国家代表性样本NHANES的发现是一致的。一个“你形” 在孕产妇多种维生素补充剂的频率和ASD风险之间发现了关系；这基于测得的母体血浆叶酸水平的发现进一步支持了关联。此外，PI组的初步数据表明，母体叶酸的摄入量可能会影响 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甲基化动力学的改变。 RNA/DNA甲基化谱将使用全转录组和全基因组含Bisulfite确定测序，蛋白质翻译将使用多构体分析确定，并在叶酸相关的变化中确定 NSC增殖和分化将被表征。 Utero叶酸与暴露相关的RNA/DNA 将使用小鼠模型确定甲基化改变。 AIM 2将确定RNA甲基化位点与脐带血样品中的叶酸叶酸暴露有关。产前叶酸状况的相互关系， RNA/DNA甲基化和儿童ASD风险将通过单个临床特征的整合确定带有相应的RNA甲基化和DNA甲基化信息。这项拟议的研究，如果成功的话，提供有关环境暴露（此处以叶酸的示例）如何参与的新见解 RNA修饰和RNA/DNA甲基化动力学的功能活性又可能与具有不良健康结果（以此为例，ASD以此为例）。开发的方法将很有帮助研究其他微量营养素或毒物的其他健康结果的分子基础。

项目成果

期刊论文数量（8）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Systematic evaluation of parameters in RNA bisulfite sequencing data generation and analysis.

DOI：
10.1093/nargab/lqac045
发表时间：
2022-06
期刊：
NAR genomics and bioinformatics
影响因子：
4.6
作者：
通讯作者：

Healthy diet during pregnancy-navigating the double-edged sword.

怀孕期间的健康饮食——驾驭双刃剑。

DOI：
10.1093/ajcn/nqab168
发表时间：
2021
期刊：
The American journal of clinical nutrition
影响因子：
0
作者：
Wang,Xiaobin
通讯作者：
Wang,Xiaobin

nMOWChIP-seq: low-input genome-wide mapping of non-histone targets.

DOI：
10.1093/nargab/lqac030
发表时间：
2022-06
期刊：
NAR genomics and bioinformatics
影响因子：
4.6
作者：
Liu Z;Naler LB;Zhu Y;Deng C;Zhang Q;Zhu B;Zhou Z;Sarma M;Murray A;Xie H;Lu C
通讯作者：
Lu C

Independent and joint association of cord plasma pantothenate and cysteine levels with autism spectrum disorders and other neurodevelopmental disabilities in children born term and preterm.