HOMOCYSTEINE AND CONGENITAL HEART DEFECTS

补充叶酸可显著减少锥体、口面和神经管缺陷。氨基酸同型半胱氨酸随着叶酸缺乏而增加，而高同型半胱氨酸本身似乎是这些缺陷的危险因素。我们最近的研究表明，同型半胱氨酸可能通过作为n -甲基- d -天冬氨酸谷氨酸受体（NMDAR）的拮抗剂而干扰神经嵴和神经管的发育。事实上，一些已知的神经嵴和神经管异常的危险因素也是NMDAR拮抗剂。本研究将验证同型半胱氨酸作为NMDAR拮抗剂诱导锥体和相关缺陷的假设。这些实验将采用鸡和小鼠胚胎模型。本提案有三个目的：目的1，验证NMDAR激动剂将拯救同型半胱氨酸处理过的胚胎的假设，相反，外源性NMDAR拮抗剂将与同型半胱氨酸协同作用，加剧对正常发育的破坏。目的2：验证同型半胱氨酸和外源性NMDAR拮抗剂在神经嵴迁移和神经管闭合过程中破坏关键基因表达的假设。目的2，确定同型半胱氨酸和外源性NMDAR拮抗剂对神经嵴细胞功能的影响。这一建议提供了第一个关于异常发育的一系列重要危险因素机制的统一假设，包括治疗和娱乐药物，环境污染物和低叶酸。一个共同的作用机制表明，这些因素可能以以前未曾预料到的方式相互作用。该提案将开始探索基因/环境相互作用在诱导这些异常中的作用。虽然叶酸补充剂会导致更少的异常，但最有效和全面的预防策略将通过对异常发育机制的透彻理解来实现。

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..