Gene-nutrient Etiologies of Neural Tube Defects

神经管缺陷的基因营养病因学

• 批准号: 6965974
• 负责人: GARY M SHAW
• 金额: $ 39.34万
• 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/6965974
• 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，其病因仍然很大程度上未知。关于 NTD 病因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女性怀孕时受 NTD 影响的风险降低。然而，叶酸降低风险的潜在机制尚不清楚。同样不为人知的是，为什么服用叶酸的女性中有相当大比例的妊娠仍受 NTD 影响。本研究提出了一个广泛的 NTD 基因和危险因素发现计划，重点通过以下方式研究 NTD 的病因：1）研究与叶酸途径相关的新遗传多态性； 2）探索膳食中胆碱和血糖指数等重要营养因素的摄入量，控制叶酸摄入量； 3) 与未产下患有 NTD 的胎儿/婴儿的妇女相比，测量产下患有 NTD 的胎儿/婴儿的妇女的妊娠中期血清中的特定营养物质和抗体； 4) 探索三种与叶酸转运受损相关的独特小鼠模型，以确定可应用于人类研究的新靶基因。这项为期 5 年的多学科综合研究计划将使用四个基于人群的大型流行病学数据集，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，以及将利用独特的遗传小鼠模型进一步了解流行病学方向。该研究项目有四个合作机构：加州出生缺陷监测项目、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。该研究利用了研究人员在分子和营养流行病学、临床、分子和小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 遗传和营养原因的科学理解。由于被忽视的热带疾病会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极大地造福社会。