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.

项目总结/摘要 神经管缺陷，包括脊柱裂和无脑畸形，是常见的和严重的出生缺陷， 当神经板，大脑和脊髓的胚胎前体，在早期不能闭合时， 怀孕叶酸强化和补充有助于减少全球神经管疾病的负担。 然而，估计不到50%的神经管缺陷归因于已知的风险因素。 饮用水的砷污染仍然是全球范围内的一个主要公共卫生威胁， 在动物模型中显示诱导神经管缺陷。一个新出现的假设是，砷通过 表观基因组，大量的化合物，影响基因的表达，而不改变潜在的 DNA序列在这个ViCTER应用程序中，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 为了验证DNA甲基化介导砷对发育中的神经细胞的神经毒性的假设， 系统更好地了解表观遗传学、营养和环境砷暴露的相互作用将有助于 为预防和治疗神经管缺陷提供信息。 在这项建议中，我们建立了一个新的基础科学-临床科学联盟，以评估砷是否 在正常神经管闭合的关键位点诱导可识别的DNA甲基化变化。我们将利用在 从孟加拉国的流行病学研究中收集的体外方法和生物样本来测量DNA 甲基化模式，包括全基因组亚硫酸氢盐测序和 Illumina EPIC/850 K BeadChip技术。此外，我们将研究基因中的DNA甲基化变化， 与短期高剂量叶酸治疗后砷暴露和叶酸状态相关 补充剂的妇女谁以前怀孕的孩子与神经管缺陷。 这种跨学科和合作研究，其中包括研究活动跨越基础应用 研究，将寻求确定基因参与神经管关闭，差异甲基化的关系， 砷暴露和叶酸水平的关系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，以减少神经管缺陷的全球负担，特别是在 高砷暴露。