HOMOCYSTEINE AND CONGENITAL HEART DEFECTS

描述(改编自申请人的摘要)，尽管 现在已知突变是先天性心血管疾病的主要原因。 畸形(CCVM)，相当大比例的CCVM是由 营养不良营养不足或中毒动物实验和 流行病学研究表明，叶酸缺乏与 心脏间隔和主动脉弓缺陷符合分类， 也就是说，它们可能起源于神经脊。其作用机制 叶酸I预防先天缺陷尚不清楚。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 即使在没有低叶酸的情况下也会升高H[e]。 他们推测H[e]可能是叶酸中的致畸剂 缺陷，机制可能涉及对神经的影响 冠状突起的外胚层。 将外源H[e]应用于禽卵中的胚胎，诱导出一种特异的 一组类似叶酸的心血管和神经管缺陷 高保真的缺陷。神经沟外胚层来源 H[e]对体外培养的血管平滑肌细胞的作用 回应：立即发出钙离子信号；原癌基因上调 6小时；最终，细胞增殖。这些影响似乎是 受体介导，并可被NMDA受体阻滞剂阻断。 在这项研究中，他们提出了对上述假设的进一步检验，即 威尔：1.H[e]诱导的先天性心脏病的表型特征 心血管畸形模型的建立；2.测定大鼠心脏血管畸形的作用 H[E]细胞的迁移、分化和基质表达 体内和体外的外胚间充质；3.开始定义假定的 H[E]受体，并测定阻断该受体的效果。 这项研究介绍了一个重要的CCVM原因的新模型和一个 H[e]角色的新概念。它有改进的潜力。 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.