HOMOCYSTEINE AND CONGENITAL HEART DEFECTS

描述（改编自申请人的摘要） 现在已知突变是先天性心血管疾病的主要原因， 畸形（CCVM），CCVM的一个显着比例是由于 营养不良或中毒。动物实验和 流行病学研究表明，叶酸缺乏与 心脏间隔和主动脉弓缺损符合分类， 即它们可以是神经嵴起源的。的作用机制 叶酸I预防先天性缺陷尚不清楚。然而，叶酸 缺乏总是与氨基酸的增加有关 同型半胱氨酸（H[e]）和先天缺陷婴儿的母亲可能 在没有叶酸的情况下，H[e]也会升高。 他们假设H[e]可能是叶酸中的致畸剂 缺陷，并且该机制可能涉及对神经系统的影响。 嵴源外生间充质组织。 将外源H[e]应用于鸡卵内胚胎，诱导特异性的 一组模拟叶酸的心血管和神经管缺陷 缺乏高度的忠诚。神经嵴外胚层来源 在体外用H[e]处理血管平滑肌细胞， 反应是：立即的Ca++信号; 6小时;最终，细胞增殖。这些影响似乎是 受体介导的，并可被NMDA受体阻断剂阻断。 在这项研究中，他们提出了对上述假设的进一步检验， 意志：1.描述H[e]诱导的先天性 心血管畸形在这个模型; 2.确定的影响， H[e]对细胞迁移、分化和基质表达的影响 外胚间充质组织在体内和体外;和3.开始定义假定的 H[e]受体，并确定阻断该受体的效果。 本研究介绍了一个新的模型的一个重要原因CCVM和一个 新概念的作用H[e]。它有潜力改善 预防CCVM。

DESCRIPTION (adapted from the applicant's abstract) Although genetic mutations are now known to be a major cause of congenital cardiovascular malformation (CCVM), a significant proportion of CCVM is the result of nutritional deficiency or toxicity. Animal experimentation and epidemiologic studies have shown that folate deficiency is correlated with cardiac septal and aortic arch defects that fit the classification, i.e. they may be of neural crest origin. The mechanism of action of folate I prevention of congenital defects is not know. However, folate deficiency always is associated with an increase in the amino acid homocysteine (H[e]) and mothers of congenitally defective babies may have elevated H[e] even in the absence of low folate. They hypothesized that H[e] may be the teratogenic agent in folate deficiency, and that the mechanism may involve an effect upon the neural crest-derived ectomesenchyme. Exogenous H[e] was applied to avian embryos in ovo, inducing a specific set of cardiovascular and neural tube defects that simulate folate deficiency with high fidelity. Neural crest ectomesenchyme-derived vascular smooth muscle cells were treated with H[e] in vitro and responded with: an immediate Ca++ signal; protooncogene upregulation in 6 hr; and ultimately, cell proliferation. These effects appeared to be receptor-mediated, and could be blocked with NMDA receptor blockers. For this study they propose further tests of the above hypothesis, that will: 1. Characterize the phenotype of H[e]-induced congenital cardiovascular malformation in this model; 2.Determine the effect of H[e] on the migration, differentiation and matrix expression of the ectomesenchyme in vivo and in vitro; and 3. Begin to define the putative H[e] receptor and determine the effect of blocking this receptor. This study introduces a new model of a significant cause of CCVM and a novel concept of the role of H[e]. It has the potential to improve prevention of CCVM.