Molecular Basis for Individual Susceptibility to Neural Tube Defects

个体对神经管缺陷易感性的分子基础

• 批准号: 9247226
• 负责人: Claudia T Kappen
• 金额: $ 54.05万
• 依托单位: LSU PENNINGTON BIOMEDICAL RESEARCH CTR
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-04-01 至 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9247226
• 关键词: Affect; Alleles; Animals; Biological; Birth; Brachyury protein; Clustered Regularly Interspaced Short Palindromic Repeats; Congenital Abnormality; Critical Pathways; Data Set; Defect; Development; Disease; Embryo; Epigenetic Process; Etiology; Experimental Models; Folic Acid; Food; Food Supply; Future; Gene Expression; Gene Expression Profile; Genes; Genetic; Genetic Variation; Goals; Impairment; Inbred Mouse; Inbred NOD Mice; Inbred Strain; Individual; Intervention; Link; Mesoderm; Molecular; Mouse Strains; Mutate; Mutation; Neural Tube Closure; Neural Tube Defects; Neural tube; Outcome; Outcomes Research; Pathogenesis; Pathogenicity; Pathway interactions; Pattern; Penetrance; Phenotype; Predisposition; Pregnancy; Prevention; Prevention strategy; Primitive Streaks; Process; Research; Risk; Risk Factors; Role; Source; Structure; Technology; Testing; Time; Transgenic Organisms; United States; Validation; Variant; base; design; differential expression; epigenetic regulation; folic acid supplementation; fortification; genetic signature; in vivo; innovation; migration; mouse model; mutant; neural plate; next generation sequencing; non-genetic; novel; novel strategies; predictive modeling; predictive signature; prevent; prognostic assays; prospective; public health relevance; simulation

 DESCRIPTION (provided by applicant): In many mouse models of neural tube defects, such defects occur in less than 100% of individuals, reflecting a phenomenon that geneticists call "incomplete" or "partial" penetrance. It is known that phenotype penetrance can be modulated by genetic background. However, this does not explain how, within a single inbred strain of genetically identical individuals, some have a defect while others do not. Since all mutant animals carry the same genetic alteration, the mutant allele itself cannot explain the phenomenon of partial penetrance. Therefore, other risk factors must exist in NTD-affected progeny. We hypothesize that -in the absence of genetic variation- NTD risk is associated with variable expression of genes and pathways that are critical for normal neural tube closure. Specifically, we propose that differences between individuals have great explanatory power for partial penetrance, when only some individuals manifest an NTD. Then, to identify specific factors that convey NTD risk to those individuals, it is necessary to explicitly focus on variabiliy. This idea is in contrast to conventional approaches that minimize variation, and thus provides a highly innovative conceptual framework. In our experimental paradigm it is possible, for the first time, to unequivocally identify NTD-prone individuals before the process of neural tube closure is completed. This provides us with the unique opportunity to develop and test predictive models for an individual's NTD risk. Our overarching goals are 1) to discover new risk factors from gene expression patterns in NTD-susceptible individuals, 2) to define expression signatures that can predict individual NTD susceptibility, and 3) to study the in vivo function of such risk signatures in defective neural tube closure by CRISPR/Cas transgenic technology. Determining to which extent risk signatures are shared among or unique to individuals has enormous biological significance, as these alternatives prompt fundamentally different strategies for prevention of NTDs: common risk factors would implicate specific biological pathways, whereas with individually distinct risk signatures, one would have to target the epigenetic mechanisms that cause variability. The need for more effective prevention is highlighted by the findings that folic acid supplements and food fortification together can prevent only 30% of the neural tube defects in the US, resulting in 3000 pregnancies affected by a defective neural tube closure every year in the US alone. A better understanding of the molecular mechanisms that confer susceptibility is required for development of new targeted strategies to prevent neural tube defects.

 描述（由申请人提供）：在许多神经管缺陷的小鼠模型中，这种缺陷发生在不到100%的个体中，反映了遗传学家称之为“不完全”或“部分”遗传的现象。已知遗传背景可调节表型突变率。然而，这并不能解释为什么在一个基因相同的个体的单一近交系中，有些人有缺陷，而另一些人没有。由于所有的突变动物都携带相同的基因改变，突变等位基因本身不能解释部分突变现象。因此，其他危险因素必须存在于NTD影响的后代。我们假设，在没有遗传变异的情况下，NTD风险与对正常神经管闭合至关重要的基因和途径的可变表达相关。具体来说，我们建议，个人之间的差异有很大的解释力，当只有一些人表现出NTD的部分abnormaltrance。然后，为了确定将NTD风险传递给这些人的特定因素，有必要明确关注可变性。这一想法与最小化变化的传统方法相反，因此提供了一个高度创新的概念框架。在我们的实验范式中，第一次有可能在神经管闭合过程完成之前明确识别出有神经管畸形倾向的个体。这为我们提供了独特的机会来开发和测试个人NTD风险的预测模型。我们的首要目标是1）从NTD易感个体的基因表达模式中发现新的风险因素，2）定义可以预测个体NTD易感性的表达特征，3）研究这些风险特征的体内功能 通过CRISPR/Cas转基因技术，确定风险特征在多大程度上是个体共有的或独特的具有巨大的生物学意义，因为这些替代方案提示了预防NTD的根本不同的策略：共同的风险因素将涉及特定的生物学途径，而对于个体不同的风险特征，人们必须针对导致变异性的表观遗传机制。叶酸缺乏的研究结果强调了更有效预防的必要性， 在美国，酸补充剂和食物强化一起只能预防30%的神经管缺陷，仅在美国，每年就有3000名孕妇受到神经管闭合缺陷的影响。更好地理解赋予易感性的分子机制是开发新的靶向策略以预防神经管缺陷所必需的。