Gene-nutrient Etiologies of Neural Tube Defects

描述(申请人提供)：神经管缺陷(NTD)是一种常见的人类先天畸形，其病因仍不清楚。关于NTDS病因的最有希望的线索之一是，在怀孕早期使用含有叶酸的维生素的妇女降低了NTD影响怀孕的风险。然而，叶酸降低风险的潜在机制尚不清楚。同样未知的是，为什么服用叶酸的女性中有相当大比例的人继续有NTD影响的怀孕。这项研究提出了一个广泛的NTD基因和风险因素发现计划，通过以下方式关注NTDS的病因：1)研究与叶酸途径相关的新的遗传多态；2)探索重要营养因素的饮食摄入量，如胆碱和血糖指数，控制叶酸摄入量；3)比较分娩患有NTDS的胎儿/婴儿和没有NTDS的妇女孕中期血清中的特定营养素和抗体；以及4)探索与叶酸运输受损有关的三种独特的小鼠模型，以确定可应用于我们的人类研究的新的靶基因。这项为期5年的多学科综合研究计划将使用四个大型基于人群的流行病学数据集，其中包含1559名患有NTDS的婴儿或胎儿和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，并将利用独特的小鼠遗传模型进一步提供流行病学方向的信息。该研究项目有四个合作机构，分别是加州出生缺陷监测计划、德克萨斯农工大学生物科学与技术研究所、奈梅亨大学和奥克兰儿童医院研究所。这项研究利用了研究人员在分子和营养流行病学、临床、分子和小鼠遗传学以及畸胎学方面的集体专业知识。这项研究计划将加强对NTDS的遗传和营养原因的科学理解。由于非传染性疾病会导致相当大的发病率以及高昂的情感和经济成本，进一步的科学理解导致可能的预防将大大有益于社会。

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.