Interdisciplinary approaches for understanding how arsenic and micronutrients affect the epigenome to influence spina bifida risk

了解砷和微量营养素如何影响表观基因组以影响脊柱裂风险的跨学科方法

• 批准号: 10560333
• 负责人: Maitreyi Mazumdar
• 金额: $ 79.92万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-01-20 至 2025-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10560333
• 关键词: Acceleration; Address; Adoption; Affect; Anencephaly and spina bifida X linked; Animal Model; Applied Research; Area; Arsenic; Bangladesh; Basic Science; Biological; Biological Markers; Biometry; Boston; Brain; California; Child; Chromatin; Clinical Sciences; Collaborations; Congenital Abnormality; Country; DNA; DNA Methylation; DNA Sequence; Development; Developmental Biology; Dose; Embryo; Epigenetic Process; Exposure to; Folic Acid; Gene Expression; Genes; Genetic; Genetic Transcription; Genomic DNA; Goals; Health; Hospitals; Human; In Vitro; Infant; Intake; Intervention; Lesion; Leukocytes; Live Birth; Measures; Mediating; Medicine; Methodology; Methods; Methylation; Micronutrients; Modeling; Molecular Biology; Molecular Epidemiology; Mothers; Mutation; Nervous System; Neural Tube Closure; Neural Tube Defects; Neurodevelopmental Disorder; Neurosciences; Operative Surgical Procedures; Outcome; Parents; Pediatric Hospitals; Pediatric Neurology; Persons; Pilot Projects; Population; Pregnancy; Prevalence; Prevention strategy; Public Health; Questionnaires; Recording of previous events; Research Activity; Risk; Risk Factors; Sampling; Schizophrenia; Science; Secondary Prevention; Spinal Cord; Spinal Dysraphism; Supplementation; Technology; Testing; Tissues; Toxic effect; Translations; Universities; Woman; autism spectrum disorder; bead chip; biobank; bisulfite sequencing; clinical examination; college; contaminated drinking water; directed differentiation; disability; effective intervention; epidemiology study; epigenome; first-in-human; folic acid supplementation; fortification; functional genomics; gene discovery; genomic locus; high reward; high risk; human embryonic stem cell; in silico; interdisciplinary approach; medical schools; methylation pattern; mortality; nerve stem cell; neural; neural plate; neuroimaging; neurosurgery; neurotoxicity; nutrition; prevent; preventive intervention; standard of care; success; whole genome

PROJECT SUMMARY/ABSTRACT Neural tube defects, including spina bifida and anencephaly, are common and severe birth defects that occur when the neural plate, the embryonic precursor to the brain and spinal cord, fails to close during early gestation. Folic acid fortification and supplementation have helped to reduce the global burden of neural tube defects; however, less than 50% of neural tube defects are estimated to be attributed to known risk factors. Arsenic contamination of drinking water continues to be a major public health threat worldwide and has been shown to induce neural tube defects in animal models. An emerging hypothesis is that arsenic acts via the epigenome, the multitude of compounds that affect the expression of genes without changing the underlying DNA sequence. In this ViCTER application, we have established a team of experts in child neurology, neurosurgery, epigenetics, developmental and molecular epidemiology, functional genomics and biostatistics to test the hypothesis that DNA methylation mediates the neurotoxicity of arsenic on the developing nervous system. Better understanding of the interplay of epigenetics, nutrition, and environmental arsenic exposure will inform strategies to prevent and treat neural tube defects. In this proposal, we establish a new basic science-clinical science consortium to assess whether arsenic induces recognizable DNA methylation changes at loci critical for normal neural tube closure. We will utilize in vitro methods and biological samples collected from an epidemiological study in Bangladesh to measure DNA methylation patterns using cutting-edge methodologies, including whole genome bisulfite sequencing and the Illumina EPIC/850K BeadChip technology. Additionally, we will investigate DNA methylation changes in genes associated with arsenic exposure and folate status following a short course of high-dose folic acid supplementation in women who previously conceived a child with a neural tube defect. This interdisciplinary and collaborative study, which includes research activities spanning basic to applied research, will seek to identify genes involved in neural tube closure that are differentially methylated in relation to arsenic exposure and folate status. This consortium effort will accelerate the translation of findings into folic acid-based preventive strategies to reduce the global burden of neural tube defects, particularly in areas with high arsenic exposure.

项目概要/摘要 神经管缺陷，包括脊柱裂和无脑畸形，是常见且严重的出生缺陷 当神经板（大脑和脊髓的胚胎前体）在早期无法关闭时 妊娠。叶酸强化和补充有助于减轻神经管的整体负担 缺陷；然而，据估计，不到 50% 的神经管缺陷是由已知的风险因素造成的。 饮用水砷污染仍然是全球主要的公共卫生威胁，并且已 在动物模型中显示可诱导神经管缺陷。一个新出现的假说是砷通过 表观基因组，影响基因表达而不改变潜在基因的多种化合物 DNA 序列。在这个 ViCTER 应用中，我们建立了一个儿童神经病学专家团队， 神经外科、表观遗传学、发育和分子流行病学、功能基因组学和生物统计学 检验 DNA 甲基化介导砷对神经发育的神经毒性的假设 系统。更好地了解表观遗传学、营养和环境砷暴露之间的相互作用将有助于 提供预防和治疗神经管缺陷的策略。 在这项提案中，我们建立了一个新的基础科学-临床科学联盟来评估砷是否 在对正常神经管闭合至关重要的位点诱导可识别的 DNA 甲基化变化。我们将利用在 体外方法和从孟加拉国流行病学研究中收集的生物样本来测量 DNA 使用尖端方法学甲基化模式，包括全基因组亚硫酸氢盐测序和 Illumina EPIC/850K BeadChip 技术。此外，我们将研究基因中 DNA 甲基化的变化 与短期大剂量叶酸疗程后的砷暴露和叶酸状态相关 以前怀过神经管缺陷孩子的女性补充。 这项跨学科和协作研究，包括从基础到应用的研究活动 研究，将寻求识别与神经管闭合相关的基因，这些基因在相关关系中存在差异甲基化 砷暴露和叶酸状况。该联盟的努力将加速将研究结果转化为叶酸 以酸为基础的预防策略，以减轻神经管缺陷的全球负担，特别是在有神经管缺陷的地区 高砷暴露。