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

基本信息

批准号：
9451317
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
项目类别：
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/9451317
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

项目摘要

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（由适用提供）：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“不完整”或“部分”渗透率的现象。众所周知，表型的外渗可以通过遗传背景调节。但是，这并不能解释如何在单个遗传相同个体的近交菌株中，有些有缺陷，而另一些则没有。由于所有突变动物都具有相同的遗传改变，因此突变等位基因本身无法解释部分渗透的现象。因此，在受NTD影响的后代中必须存在其他危险因素。我们假设 - 在没有遗传变异的情况下，风险与基因和途径的可变表达有关，这对于正常中性管闭合至关重要。具体而言，我们建议，当只有某些人表现出NTD时，个体之间的差异具有很大的爆炸能力。然后，为了确定向这些人传达NTD风险的特定因素，有必要明确关注变异性。这个想法与最小化变化的常规方法相反，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，在神经管闭合过程完成之前，有可能首次明确地识别易于NTD的个体。这为我们提供了为个人NTD风险开发和测试预测模型的独特机会。我们的总体目标是1）发现从NTD启发性个体中基因表达模式的新风险因素，2）定义可以预测个体NTD易感性的表达签名，以及3）研究此类风险特征的体内功能在CRISPR/CAS转基因技术中闭合中性管有缺陷。确定在哪种程度之间共享或在个人中所独有的风险标志具有增强的生物学意义，因为这些替代方案促使预防NTD的根本不同的策略：共同的风险因素将暗示特定的生物学途径，而具有单独的不同风险特征，因此必须针对引起可变性的表观遗传机制。叶面的发现强调了对更有效预防的需求酸补充剂和食物防御能力共同可以预防美国的神经元管缺陷的30％，导致每年仅在美国，每年每年都会受到3000名受神经元管闭合的影响。更好地理解会议易感性的分子机制是开发新的靶向策略以防止神经元管缺陷的。