Gene-nutrient Etiologies of Neural Tube Defects

描述（由申请人提供）：神经管缺陷（NTD）是常见的人类先天性异常，其病因在很大程度上仍未知。NTD病因最有希望的线索之一是，在怀孕早期使用含叶酸维生素的妇女患NTD的风险降低。然而，叶酸降低风险的潜在机制尚不清楚。同样不清楚的是，为什么服用叶酸的妇女中有很大一部分仍然有NTD影响的怀孕。本研究提出了一个广泛的NTD基因和危险因素发现计划，重点是NTD的病因学：1）研究与叶酸途径相关的新的遗传多态性：2）探索重要营养因素如胆碱和血糖指数的膳食摄入，控制叶酸摄入量; 3）测量来自分娩NTD胎儿/婴儿的妇女与未分娩NTD胎儿/婴儿的妇女相比的孕中期血清中的特异性营养素和抗体;和4）探索与受损的叶酸转运有关的三种独特的小鼠模型，以鉴定可应用于我们的人类研究的新靶基因。这项多学科和综合性的5年研究计划将使用四个大型的基于人群的流行病学数据集，其中包含1559名NTD婴儿或胎儿和3353名非畸形对照婴儿的数据，并结合最先进的人类DNA实验室基因分型方法，并将利用独特的遗传小鼠模型进一步为流行病学方向提供信息。该研究计划有四个合作机构，加州出生缺陷监测计划，德克萨斯A&M大学生物科学与技术研究所，奈梅亨大学和儿童医院奥克兰研究所。这项研究利用了研究人员在分子和营养流行病学、临床、分子和鼠遗传学以及畸形学方面的集体专业知识。这项研究计划将提高对NTD遗传和营养原因的科学认识。由于NTDs导致大量的发病率以及高昂的情感和经济成本，进一步的科学认识导致可能的预防将大大有利于社会。

DESCRIPTION (provided by applicant): Neural tube defects (NTDs) are common human congenital anomalies whose etiologies remain largely unknown. One of the most promising clues to the causes of NTDs is that women who use vitamins containing folic acid in early pregnancy are at reduced risk for NTD-affected pregnancies. However, the underlying mechanisms by which folic acid reduces risks are unknown. Also unknown is why a substantial proportion of women who take folic acid continue to have NTD-affected pregnancies. This research proposes an extensive NTD gene and risk factor discovery program which focus on etiologies of NTDs by: 1) studying new genetic polymorphisms related to the folate pathway; 2) exploring dietary intake of important nutritional factors such as choline and glycemic index, controlling for folate intake; 3) measuring specific nutrients and antibodies in midpregnancy sera from women who deliver fetuses/infants with NTDs compared to those who do not; and 4) exploring three unique mouse models pertaining to impaired folate transport to identify new target genes that can be applied to our human studies. This multidisciplinary and integrated 5- year research program will use four large population-based epidemiologic datasets containing data on 1559 infants or fetuses with NTDs and 3353 nonmalformed control infants in combination with state-of-the-art laboratory genotyping methods of human DNA, and will capitalize on unique genetic mouse models to further inform epidemiologic direction. The research program has four collaborating institutions, the California Birth Defects Monitoring Program, the Institute of Biosciences and Technology at Texas A&M University, University of Nijmegen, and Children's Hospital Oakland Research Institute. The research capitalizes on the investigators' collective expertise in molecular and nutritional epidemiology, clinical, molecular, and murine genetics, and teratology. This research program will enhance scientific understanding of the genetic and nutritional causes of NTDs. Because NTDs result in substantial morbidity as well as high emotional and economic costs, further scientific understanding leading to possible prevention would greatly benefit society.