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Genetic Predisposition & Prevention of Neural Tube Defects (NTDs)

遗传易感性

基本信息

批准号：
7906757
负责人：
JOSEPH H. NADEAU
金额：
$ 118.1万
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：
2009
资助国家：
美国
起止时间：
2009-08-01 至 2011-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7906757
关键词：
Adult Alleles Biochemical Pathway Biological Biological Markers Blood Blood specimen Carbon Cardiovascular Diseases Cells Clinical Cluster Analysis Complement Complex Congenital Abnormality Congenital Heart Defects Data Defect Dietary Supplementation Disease Embryo Employee Strikes Environment Ethylnitrosourea Failure Family Fibroblasts Folate Folic Acid Gene Expression Gene Expression Profile Genes Genetic Genetic Polymorphism Genetic Predisposition to Disease Goals Hereditary Disease Homocysteine Homocystine Human Individual Inositol Institution Laboratories Lead Liver Malignant Neoplasms Measures Metabolic Metabolic Pathway Metabolism Methionine Methods Modeling Molecular Molecular Genetics Molecular Models Molecular Profiling Mood Disorders Mus Mutagenesis Mutant Strains Mice Mutation Neural Tube Closure Neural Tube Defects Neural tube Pathway interactions Pattern Point Mutation Population Predictive Value of Tests Prevention Prevention therapy Preventive Prophylactic treatment Publishing Regulation Resistance Resources Risk Risk Assessment Risk Factors Sampling Siblings Signal Transduction Supplementation Tail Testing Therapeutic Effect Tissues Transcript base developmental genetics experience gain of function mutation improved interest molecular modeling mouse model mutant offspring prevent receptor relating to nervous system research study response trait

项目摘要

Failure of neural tube closure is a complex genetic disorder, rarely if ever seen as a simple Mendelian trait. In the clinical population, NTDs are probably most often caused by partial inactivation and/or gain of function mutations of multiple genes, acting in conjunction with the gestational environment. Recognizing such changes as disease associated mutations rather than simple polymorphisms is a challenge for assessment of risk in individual families. Another challenge is determining the most appropriate means to reduce NTD occurrence for a particular couple. Recent studies from these three collaborating laboratories lead us to hypothesize that a systematic examination of gene network interactions in mouse models will elucidate patterns that are applicable to risk assessment and prevention of NTDs in humans. In a mouse line with a folic acid (FA) responsive NTD, we identified a point mutation in Lrp6, a co-receptor for Wnt canonical signaling, which implicates several important developmental genetic pathways likely to be encountered clinically. Using this Crooked tail (Cd) mouse, we identified a possible gene expression and metabolism “signature” in liver tissue and blood, predicting a genetic make-up that will respond to FA supplementation by preventing NTD. In addition, we used ENU mutagenesis screens to identify NTD associated mouse mutations that provide candidates for human testing and which can be tested for response to FA and other potential NTD preventive agents. We propose to pursue a multi-institution effort to characterize genetic susceptibility profiles in mice and identify genetic backgrounds that respond to prevention measures such as dietary supplementation. Experiments will use FA and inositol supplementation to test whether these agents prevent NTD in Lrp6 null and NTD-prone mice with defined ENU-generated mutations. Gene transcript arrays will examine expression in the neural tube during closure in these mutants using cluster analysis to compare patterns in the mutant vs. wildtype siblings. In addition, the genetic and metabolic signature identified in Cd non-neural tissues will be compared against signatures in other ENU-generated and naturally occurring NTD mouse mutants to determine the predictive power of this pattern. This project will build a framework for rational approaches to new treatments based on molecular pathways. To this end, the relationship between the biochemical pathway that is disrupted and the responsiveness or resistance to FA supplementation will be examined in several mouse lines. This will begin to reveal mechanisms by which FA, and inositol, acts to suppress NTD.

神经管关闭失败是一种复杂的遗传疾病，很少被视为简单的孟德尔特征。在临床人群中，ntd可能最常由多个基因的部分失活和/或功能突变的获得引起，与妊娠环境共同作用。认识到这些变化是与疾病相关的突变，而不是简单的多态性，是评估单个家庭风险的一个挑战。另一个挑战是确定最合适的方法来减少特定夫妇的NTD发生。这三个合作实验室最近的研究使我们假设，对小鼠模型中基因网络相互作用的系统检查将阐明适用于人类被忽视热带病风险评估和预防的模式。