Homocysteine and NMDA receptor in cardiac neural crest development

同型半胱氨酸和 NMDA 受体在心脏神经嵴发育中的作用

• 批准号: 6611204
• 负责人: DANIEL T MONAGHAN
• 金额: $ 20.43万
• 依托单位: UNIVERSITY OF NEBRASKA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-09-01 至 2003-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6611204
• 关键词: NMDA receptors; cell migration; chick embryo; congenital heart septum defect; embryo /fetus; embryo /fetus toxicology; genetically modified animals; homocysteine; laboratory mouse; neural crest; protein isoforms; teratogens; vertebrate embryology

Neural crest cell formation and migration is necessary for the normal development of cardiac septation. Neural crest ablation causes subsequent cardiac septation defects. Since homocysteine causes both neural crest- related midline closure defects and the neural crest-related cardiac defects, homocysteine appears to be preventing the normal migration and differentiation of neural crest cells. This hypothesis is consistent with preliminary data from in vitro experimental thus, the central hypothesis for this project is that homocysteine causes NGA conotruncal defects by altering the migration and/or differentiation of cardiac cells of neural crest origin. Based upon the following observations, we further hypothesize that the actions of homocysteine are mediated by an N- methyl-D-aspartate (NMDA) receptor. 1) NMDA receptor antagonists cause the same set of neural crest-related defects as homocysteine, 2) homocysteine is an NMDA receptor antagonist, 3) NMDA receptors play a key role in the Ca++-dependent migration of other cells during development, 4) neural crest cells display Ca++-dependent migration, and 5) neural crest cells express NMDA receptors. The following experiments are designed to test these hypotheses and to describe the key components of this system. 1. We will determine if homocysteine exposure alterations the formation, emigration, and/or migration of neural crest cells in stage 9-12 avian embryos. 2. Are homocysteine's actions on NC cells mimicked, or blocked, by NMDA receptor agents and by NMDA receptor subunit knockout? 3. We will identify the subtype of NMDA receptor that is expressed in NC cells and determine its ability to directly interact with homocysteine and to cause the developmental defects.

神经嵴细胞的形成和迁移是心间隔正常发育的必要条件。神经嵴消融引起继发性心间隔缺损。由于同型半胱氨酸可引起神经嵴相关的中线闭合缺陷和神经嵴相关的心脏缺陷，因此同型半胱氨酸似乎可以阻止神经嵴细胞的正常迁移和分化。这一假设与体外实验的初步数据一致，因此，本项目的中心假设是，同型半胱氨酸通过改变神经嵴来源的心脏细胞的迁移和/或分化而导致NGA锥体缺陷。基于以下观察，我们进一步假设同型半胱氨酸的作用是由N-甲基- d -天冬氨酸（NMDA）受体介导的。1) NMDA受体拮抗剂引起与同型半胱氨酸相同的神经嵴相关缺陷，2)同型半胱氨酸是一种NMDA受体拮抗剂，3)NMDA受体在发育过程中其他细胞的Ca依赖性迁移中起关键作用，4)神经嵴细胞表现Ca依赖性迁移，5)神经嵴细胞表达NMDA受体。下面的实验旨在验证这些假设，并描述该系统的关键组成部分。1. 我们将确定同型半胱氨酸暴露是否会改变9-12期禽类胚胎神经嵴细胞的形成、迁移和/或迁移。2. 同型半胱氨酸对NC细胞的作用是否被NMDA受体药物和NMDA受体亚基敲除模拟或阻断？3. 我们将确定在NC细胞中表达的NMDA受体亚型，并确定其直接与同型半胱氨酸相互作用并导致发育缺陷的能力。