CARDIAC NEURAL CREST IN DEVELOPMENT OF MYOCARDIAL FUNCTI

心肌功能发育中的心脏神经嵴

• 批准号: 6727743
• 负责人: Tony L Creazzo
• 金额: $ 44.64万
• 依托单位: AUGUSTA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-04-01 至 2005-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6727743
• 关键词: calcium channel; calcium flux; chick embryo; congenital heart disorder; embryo /fetus tissue /cell culture; fluorescence spectrometry; heart contraction; heart electrical activity; heart ventricle; hemodynamics; histogenesis; myogenesis; neural crest; sarcolemma; sarcoplasmic reticulum; tissue /cell culture; vertebrate embryology; voltage /patch clamp

Three out of the top four most lethal heart defects are neural crest-related and account for 70% of the total cost of treating congenital heart disease. Prior work identified impaired cardiac excitation-contraction (EC) coupling as the major functional deficit in neural crest-ablated chick embryo. Markedly reduced intracellular Ca2+ transients due to reduced L-type Ca2+ current, decreased Ca2+ uptake into the sarcoplasmic reticulum (SR) and reduced SR Ca2+-induced Ca2+ release (CICR) was documented in myocytes and isolated trabeculae. Furthermore, the average force per crossbridge was decreased. Aim 1 will test the new hypothesis that reduced cardiac L-type Ca2+ current is due to decreased function and/or expression of L-type Ca2+ channels in embryonic heart after neural crest ablation. Experiments are designed to determine if newly synthesized Ca2+ channels are inserted into the sarcolemma; whether single channel activity is reduced; and whether there is altered expression of Ca2+ channel subunits in neural crest-ablated embryos. Aim 2 will test the new hypothesis that CICR is impaired irrespective of the availability of extracellular "trigger" Ca2+ following neural crest ablation. Experiments are designed to determine whether there is decreased Ca2+ sensitivity of CICR; whether peripheral couplings between surface membrane and SR are mature; and whether gain of CICR is reduced. Aim 3 will test the new hypothesis that one of two mechanisms impairs force produce by the contractile apparatus in embryonic ventricle following crest ablation. It will be determined whether cross-bridge function is normal but parallel elasticity (that absorbs much of the work produced by the cross-bridges) is increased; or whether cross-bridge function is abnormal. The results from these studies will provide new information that could lead to improved care and treatment of infants with congenital heart disease.

在四种最致命的心脏缺陷中，有三种与神经嵴有关，占治疗先天性心脏病总费用的70%。先前的工作确定受损的心脏兴奋收缩（EC）耦合作为主要的功能缺陷，在神经嵴消融鸡胚。在肌细胞和分离的肌小梁中记录了由于L型Ca 2+电流减少、肌浆网（SR）中Ca 2+摄取减少和SR Ca 2+诱导的Ca 2+释放（CICR）减少而导致的细胞内Ca 2+瞬变显著减少。此外，每个横桥的平均力降低。目的1：验证胚胎心脏L型钙通道功能和/或表达的降低是神经嵴消融后L型钙通道电流降低的原因。实验的目的是确定是否新合成的Ca 2+通道插入到肌膜;是否单通道活性降低;以及是否有改变表达的Ca 2+通道亚基在神经嵴消融胚胎。目标2将测试新的假设，即CICR受损，无论神经嵴消融后细胞外“触发”Ca 2+的可用性如何。实验旨在确定CICR的Ca 2+敏感性是否降低，表面膜和SR之间的外围耦合是否成熟，以及CICR的增益是否降低。目的3将验证脊切除后两种机制中的一种损害胚胎心室收缩器产生的力的新假设。将确定横桥功能是否正常，但平行弹性（吸收横桥产生的大部分功）增加;或横桥功能是否异常。这些研究的结果将提供新的信息，可能导致改善先天性心脏病婴儿的护理和治疗。