HOMOCYSTEINE AND CONGENITAL HEART DEFECTS

同型半胱氨酸与先天性心脏缺陷

• 批准号: 6095379
• 负责人: THOMAS H. ROSENQUIST
• 金额: $ 35.25万
• 依托单位: UNIVERSITY OF NEBRASKA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 1995
• 资助国家: 美国
• 起止时间: 1995-09-30 至 2004-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6095379
• 关键词: NMDA receptors; cell differentiation; cell migration; chick embryo; congenital cardiovascular disorder; congenital disorders; congenital heart disorder; congenital oral /facial /cranial defect; developmental genetics; developmental neurobiology; folate deficiency; gene environment interaction; gene expression; homocysteine; laboratory mouse; mesenchyme; neural crest; neural plate /tube; neurotransmitter agonist; neurotransmitter antagonist; teratogens; vertebrate embryology

Supplemental folic acid is associated with significant decreases in conotruncal, orofacial, and neural tube defects. The amino acid homocysteine increases with folate deficiency, and elevated homocysteine per se appears to be a risk factor for these defects. Our recent studies have led to the hypothesis that homocysteine may perturb neural crest and neural tube development by acting as an antagonist for the N-methyl-D-aspartate glutamate receptor (NMDAR). Indeed, some of the best known risk factors for neural crest and neural tube abnormalities also are NMDAR antagonist. The present proposal will test the hypothesis that homocysteine induces conotruncal and related defects by acting as an NMDAR antagonist. Both the chicken and the mouse embryo models will be employed in these experiments. There are three aims of this proposal: Aim 1, to test the hypotheses that NMDAR agonists will rescue homocysteine-treated embryos, and conversely, that exogenous NMDAR antagonists will interact synergistically with homocysteine to exacerbate the disruption of normal development. Aim 2, to test the hypothesis that homocysteine and exogenous NMDAR antagonists disrupt the expression of key genes during hypothesis that homocysteine and exogenous NMDAR antagonists disrupt the expression of key genes during neural crest migration and neural tube closure. Aim 2, to determine the effect of homocysteine and exogenous NMDAR antagonists on neural crest cell functions. This proposal offers the first unifying hypothesis regarding a mechanism for a set of important risk factors for abnormal development that includes therapeutic and recreational drugs, environmental contaminants, and low folate. A common mechanism of actions would show that these factors may interact in previous unsuspected ways. This proposal will begin to explore the role of gene/environment interactions in the induction of these abnormalities. Although folate supplements will result in fewer abnormalities, the most effective and comprehensive prevention strategies will come through a thorough understanding of the mechanisms that underlie abnormal development..

补充叶酸与共鸣，口面和神经管缺陷的显着降低有关。氨基酸的同型半胱氨酸随叶酸缺乏而增加，而同型半胱氨酸本身似乎是这些缺陷的危险因素。我们最近的研究提出了这样的假设，即同型半胱氨酸可能通过充当N-甲基-D-天冬氨酸谷氨酸受体（NMDAR）的拮抗剂来扰动神经rest和神经管的发育。实际上，神经rest和神经管异常的一些最著名的危险因素也是NMDAR拮抗剂。本提案将检验以下假设，即同型半胱氨酸通过充当NMDAR拮抗剂诱导共骨和相关的缺陷。这些实验将使用鸡肉和小鼠胚胎模型。该提案的目的有三个：目标1，以测试NMDAR激动剂将营救同型半胱氨酸治疗的胚胎的假设，相反，外源性NMDAR拮抗剂将与同半胱氨酸协同相互作用，以使正常发育的破坏加剧。目的2，以检验以下假设：在假设中，同型和外源性NMDAR拮抗剂破坏了关键基因的表达，即在假设中，同型半胱氨酸和外源性NMDAR拮抗剂破坏了神经犯罪迁移和神经管闭合过程中关键基因的表达。目的2，确定同型半胱氨酸和外源性NMDAR拮抗剂对神经rest细胞功能的影响。该提案提供了第一个统一的假设，该假设涉及一组异常发育的重要风险因素，包括治疗和休闲药物，环境污染物和低叶酸。行动的一种共同机制将表明，这些因素可能会以先前的未经注意的方式相互作用。该提案将开始探讨基因/环境相互作用在诱导这些异常中的作用。尽管叶酸补充剂会导致更少的异常，但最有效，最全面的预防策略将通过对基于异常发展的机制的彻底理解来实现。