PROJECT 1: Gene Variants & Their Interactions Defining Human NTD Risk

项目 1：基因变异

基本信息

批准号：
8379335
负责人：
MARGARET ELIZABETH ROSS
金额：
$ 47.48万
依托单位：
WEILL MEDICAL COLL OF CORNELL UNIV
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/8379335
关键词：
AXIN2 protein Actins Address Affect Age Alanine Alleles Anencephaly Animal Model Animals Antioxidants Apical Apolipoproteins B Apoptosis Autistic Disorder BMP5 gene Basic Science Biochemical Biological Biological Assay CNTNAP1 gene Carbon Categories Cell Death Cell Polarity Cell Proliferation Cells Child Clinical Clinical Research Complex Computer Simulation Custom DNA DNA Methylation DNA Resequencing Data Defect Detection Development Disease Dorsal Dose Embryo Embryonic Development Emulsions Environmental Exposure Environmental Risk Factor Enzymes Event Exons Failure Family Female of child bearing age Fetus Fibroblast Growth Factor Receptor 1 Folate Folic Acid Frequencies Gene Expression Gene Transfer Generations Genes Genetic Genetic Polymorphism Genetic Variation Genomics Genotype Guns Hereditary Disease Homocysteine Homocystine Hour Human Human Cell Line Hydrogen Peroxide In Vitro Individual Inflammation Inositol Instruction Intake Intervention Knowledge Laboratories Lead MTHFR gene Mediation Mesenchymal Metabolic Pathway Metabolism Methodology Methylation Microfilaments Modeling Molecular Molecular Target Mouse Cell Line Mus Mutate Mutation Nanotechnology Nature Neural Fold Neural Tube Closure Neural Tube Defects Neural tube Neurons Nitrogen Nutrient Oxidative Stress Oxygen Pathogenesis Pathway Analysis Pathway interactions Patients Pattern Peroxonitrite Phenotype Phosphotransferases Population Predictive Value Pregnancy Prevention Proteins Reaction Reactive Oxygen Species Regimen Risk Role Running Sampling Schizophrenia Screening procedure Shapes Signal Transduction Signaling Molecule Single Nucleotide Polymorphism Sonic Hedgehog Pathway Spinal Dysraphism Strabismus Superoxides Supplementation System Tail Testing Text Time Translating Validation Variant Vinculin Woman Work advanced system analytical tool animal data base cardiovascular disorder risk caspase-9 chromatin remodeling clinical practice combinatorial deprivation design epigenomics extracellular folic acid metabolism gain of function gene environment interaction gene interaction grasp high throughput screening in vitro testing in vivo knock-down milligram mouse model mutant nitration nitrosative stress overexpression prenatal prevent profilin programs receptor repository reproductive single molecule sonic hedgehog receptor transcription factor

项目摘要

GENE VARIANTS & THEIR INTERACTIONS DEFINING HUMAN NTD RISK Neural tube defects (NTDs), primarily spina bifida and anencephaly, arise from a complex interplay of multiple gene interactions and environmental exposures. After 30 years of clinical and basic research, the field remains unable to accurately predict the risk for an individual couple of having a child affected by NTD, how folic acid (FA) works to prevent NTDs, whether or what dose of FA is likely provide effective prevention for them or whether there is another nutrient/supplement or intervention that would provide greater benefit The recent confluence of information from genetic mouse models, capabilities of molecular biological and biochemical detection in embryonic systems and advances in genomics and computational genetics now provides sufficient power to successfully address this complex genetic disorder. Project 1 will test the following hypotheses: 1. that combinations of rare variant single nucleotide polymorphisms (SNPs) will display associations useful for the definition of individual NTD risk in humans, and 2. that recognition of interactions between these genetic patterns with environmental conditions, including FA intake and factors common to inflammation or oxidative/nitrosative stress, can further increase their predictive value. This project will use deep resequencing of NTD patient DNA, targeted to human counterparts of some 1,000 genes implicated in NTD pathogenesis by clinical and animal model studies, to identify rare variant alleles that are overrepresented in NTD patients. These will be used to design custom SNP assays for screening larger patient numbers for analyses of single gene and pair-wise associations with NTD. Computational modeling will assess the potential impact of NTD associated SNPs on key developmental and metabolic pathways. The functional significance of SNP associations in humans will be functionally tested first for impact on Wnt/PCP, FA metabolism and oxidative/nitrosative stress using in vitro and mouse systems assays that will also be used to validate and inform computational modeling. Because the overt NTD phenotypes are readily recognized in humans and experimental animals, NTDs may well be the first complex genetic disorder for which gene-gene and gene-environment interactions can be understood in depth. Progress made for this disorder can provide useful analytical tools for identifying molecular network interactions relevant to later-onset complex genetic disorders, like schizophrenia and autism. RELEVANCE (See instructions): Enhanced capabilities for assessment of individual risk for developing NTDs would permit prevention regimens to be tailored to individuals rather than applied 'shot-gun' to populations. In broadest scope, data generated in Project 1 will have implications for every reproductive-age woman worldwide. In addition, folate metabolism can exert a lasting impact on gene expression by influencing DNA methylation, making it imperative that we understand the ramifications of FA supplementation. A fuller grasp of the relationships between the FA pathway and risk genes will have important relevance for a broad range of other diseases in which folate status may have a role.

定义人类 NTD 风险的基因变异及其相互作用神经管缺陷 (NTD)，主要是脊柱裂和无脑畸形，是由复杂的相互作用引起的多基因相互作用和环境暴露。经过30年的临床和基础研究，该领域仍然无法准确预测一对夫妇生育受以下疾病影响的孩子的风险 NTD，叶酸 (FA) 如何预防 NTD，FA 是否或什么剂量可能有效对他们进行预防或是否有其他营养素/补充剂或干预措施可以提供更大的好处最近来自遗传小鼠模型、分子生物学能力的信息的融合胚胎系统中的生物和生化检测以及基因组学和计算的进展遗传学现在提供了足够的力量来成功解决这种复杂的遗传性疾病。项目 1 将测试以下假设： 1. 罕见变异单核苷酸的组合多态性 (SNP) 将显示有助于定义人类个体 NTD 风险的关联， 2. 认识到这些遗传模式与环境条件之间的相互作用，包括 FA 摄入量和炎症或氧化/亚硝化应激常见因素，可以进一步增加他们的预测价值。该项目将使用 NTD 患者 DNA 的深度重测序，针对人类通过临床和动物模型研究，发现约 1,000 个与 NTD 发病机制相关的基因的对应基因，以识别 NTD 患者中过多出现的罕见变异等位基因。这些将用于设计定制 SNP 检测可筛选更多患者，以进行单基因和成对关联分析患有新唐人病。计算模型将评估 NTD 相关 SNP 对关键疾病的潜在影响发育和代谢途径。 SNP 关联在人类中的功能意义将是首先使用体外功能测试对 Wnt/PCP、FA 代谢和氧化/亚硝化应激的影响和小鼠系统检测，也将用于验证和通知计算模型。由于明显的 NTD 表型在人类和实验动物中很容易识别， NTD很可能是第一个复杂的遗传性疾病，其基因-基因和基因-环境互动可以深入理解。这种疾病的进展可以提供有用的分析工具用于识别与晚发复杂遗传性疾病相关的分子网络相互作用，例如精神分裂症和自闭症。相关性（参见说明）：增强评估个体罹患被忽视热带病的风险的能力将有助于预防针对个人量身定制治疗方案，而不是对人群进行“散弹枪”治疗。在最广泛的范围内，数据项目 1 产生的结果将对全世界每一位育龄妇女产生影响。此外，叶酸新陈代谢可以通过影响 DNA 甲基化对基因表达产生持久影响，使其我们必须了解补充 FA 的后果。更全面地把握关系 FA 途径和风险基因之间的关系将与广泛的其他疾病具有重要的相关性。哪种叶酸状态可能有一定作用。