Risk Genes and Environment Interactions in NTDs

NTD 的风险基因和环境相互作用

• 批准号: 8687505
• 负责人: MARGARET ELIZABETH ROSS
• 金额: $ 110.97万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-10 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8687505
• 关键词: Address; Affect; Alleles; Anencephaly; Animal Model; Animals; Autistic Disorder; Basic Science; Biochemical; Biological; Biological Assay; Child; Clinical; Clinical Research; Complex; Computer Simulation; Custom; DNA; DNA Resequencing; Detection; Development; Disease; Dose; Embryo; Environmental Exposure; Folic Acid; Genes; Genetic; Genomics; Hereditary Disease; Human; In Vitro; Individual; Inflammation; Instruction; Intake; Intervention; Metabolic Pathway; Modeling; Molecular; Mus; Neural Tube Defects; Nutrient; Oxidative Stress; Pathogenesis; Patients; Pattern; Phenotype; Predictive Value; Prevention; Risk; Schizophrenia; Single Nucleotide Polymorphism; Spinal Dysraphism; System; Testing; Work; advanced system; analytical tool; design; folic acid metabolism; gene environment interaction; gene interaction; mouse model; nitrosative stress; prevent; programs; rare variant; risk variant; screening

DESCRIPTION (provided by applicant): 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.

描述（由申请人提供）：神经管缺陷（NTDs），主要是脊柱裂和无脑畸形，是由多种基因相互作用和环境暴露的复杂相互作用引起的。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的孩子患NTD的风险，叶酸（FA）如何预防NTD， FA是否或多大剂量的叶酸可能为他们提供有效的预防，或者是否有另一种营养/补充剂或干预措施可以提供更大的益处。胚胎系统中分子生物学和生物化学检测的能力以及基因组学和计算遗传学的进步现在为成功解决这种复杂的遗传疾病提供了足够的力量。项目1将测试以下假设：1 .罕见变异单核苷酸多态性（snp）的组合将显示出对人类个体NTD风险定义有用的关联。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/亚硝化应激的常见因素，可以进一步提高其预测价值。该项目将通过临床和动物模型研究，对NTD患者DNA进行深度重测序，针对与NTD发病机制有关的约1000个基因的人类对应基因，以确定在NTD患者中过度代表的罕见变异等位基因。这些将用于设计定制SNP检测，以筛选更多的患者，分析与NTD的单基因和成对关联。计算模型将评估NTD相关snp对关键发育和代谢途径的潜在影响。人类SNP关联的功能意义将首先通过体外和小鼠系统分析进行功能测试，以确定其对Wnt/PCP、FA代谢和氧化/亚硝化应激的影响，这些分析也将用于验证并为计算建模提供信息。由于明显的NTD表型在人类和实验动物中很容易被识别，因此NTD很可能是第一个可以深入了解基因-基因和基因-环境相互作用的复杂遗传疾病。这种疾病的进展可以为确定与晚发性复杂遗传疾病（如精神分裂症和自闭症）相关的分子网络相互作用提供有用的分析工具。