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: 9903420
• 负责人: Claudia T Kappen
• 金额: $ 57.63万
• 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/9903420
• 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; individual variation; innovation; migration; mouse model; mutant; neural plate; next generation sequencing; non-genetic; novel; novel strategies; predictive modeling; predictive signature; predictive test; prevent; prognostic assays; prognostic value; 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(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，反映了一种遗传学家称之为“不完全”或“部分”外显的现象。已知表型外显性受遗传背景的调节。然而，这并不能解释为什么在基因相同的单个近亲繁殖品系中，有些人有缺陷，而另一些人没有。由于所有突变的动物都带有相同的基因改变，突变的等位基因本身无法解释部分外显现象。因此，NTD的子代中一定存在其他危险因素。我们假设，在没有遗传变异的情况下，NTD风险与基因和通路的可变表达有关，这些基因和通路对正常的神经管关闭至关重要。具体地说，我们提出，当只有部分个体表现出NTD时，个体之间的差异对部分外显有很大的解释能力。然后，为了确定将NTD风险传递给这些个人的特定因素，有必要明确关注变量。这一想法与将差异最小化的传统方法形成了鲜明对比，从而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关闭过程完成之前明确地识别NTD倾向的个体。这为我们提供了一个独特的机会来开发和测试个人NTD风险的预测模型。我们的主要目标是1)从NTD易感个体的基因表达模式中发现新的危险因素，2)定义可以预测个体NTD易感性的表达特征，以及3)研究这些风险特征的体内功能 应用CRISPR/Cas转基因技术进行缺陷性神经管关闭。确定风险特征在多大程度上在个体之间共享或独特，具有巨大的生物学意义，因为这些替代方案促使采取根本不同的预防非传染性疾病的战略：共同的风险因素将涉及特定的生物途径，而对于个别不同的风险特征，人们将不得不瞄准导致变异性的表观遗传机制。叶酸的研究结果突显了更有效预防的必要性 在美国，酸性补充剂和食物强化加在一起只能预防30%的神经管缺陷，仅在美国每年就有3000例因神经管关闭缺陷而受到影响的怀孕。为了开发预防神经管缺陷的新的靶向策略，需要更好地理解赋予易感性的分子机制。