Gene-nutrient Etiologies of Neural Tube Defects

神经管缺陷的基因营养病因学

• 批准号: 7113829
• 负责人: GARY M SHAW
• 金额: $ 40.82万
• 依托单位: MARCH OF DIMES BIRTH DEFECTS FOUNDATION
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-09-01 至 2010-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7113829
• 关键词: autoantibody; choline; clinical research; congenital nervous system disorder; dietary constituent; disease /disorder etiology; embryo /fetus disorder; female; folate; gene expression; genetic polymorphism; genetic susceptibility; genotype; glucose; high throughput technology; human pregnant subject; laboratory mouse; microarray technology; mother /embryo /fetus nutrition; nervous system disorder epidemiology; neural plate /tube; nutrition related tag; outcomes research; vitamin B12; vitamin receptor; women' s health

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.

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未知。 NTD的原因最有前途的线索之一是，在怀孕早期使用含有叶酸的维生素的女性降低了受NTD影响妊娠的风险。但是，叶酸降低风险的基本机制尚不清楚。同样未知的是为什么要在很大一部分服用叶酸的妇女继续患有NTD影响的妊娠。这项研究提出了一个广泛的NTD基因和风险因素发现计划，该计划的重点是NTD的病因：1）研究与叶酸途径有关的新遗传多态性； 2）探索重要营养因素的饮食摄入，例如胆碱和血糖指数，以控制叶酸摄入； 3）与没有胎儿/婴儿的妇女相比，与没有的胎儿/婴儿相比，测量中性孕妇血清中的特定营养和抗体； 4）探索与叶酸转运受损的三种独特的小鼠模型，以识别可应用于我们的人类研究的新靶基因。 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.该研究计划有四个合作机构，加利福尼亚州的出生缺陷监测计划，得克萨斯州A＆M大学，尼加梅根大学的生物科学技术研究所以及奥克兰儿童医院研究所。该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。该研究计划将增强对NTD的遗传和营养原因的科学理解。由于NTD会导致大量的发病率以及高昂的情感和经济成本，因此进一步的科学理解会导致可能的预防，这将极大地使社会受益。