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.

四种最致命的心脏缺陷中，有三种与神经嵴相关，占治疗先天性心脏病总费用的 70%。先前的研究发现，心脏兴奋-收缩（EC）耦合受损是神经嵴消融鸡胚胎的主要功能缺陷。在肌细胞和孤立的小梁中，由于 L 型 Ca2+ 电流减少、肌浆网 (SR) 的 Ca2+ 摄取减少以及 SR Ca2+ 诱导的 Ca2+ 释放 (CICR) 减少，细胞内 Ca2+ 瞬变明显减少。此外，每个横桥的平均力也有所降低。目标 1 将检验新假设，即心脏 L 型 Ca2+ 电流减少是由于神经嵴消融后胚胎心脏中 L 型 Ca2+ 通道功能和/或表达下降所致。实验旨在确定新合成的 Ca2+ 通道是否插入肌膜中；单通道活动是否减少；以及神经嵴消融胚胎中 Ca2+ 通道亚基的表达是否发生改变。目标 2 将检验新假设，即无论神经嵴消融后细胞外“触发”Ca2+ 的可用性如何，CICR 都会受损。实验旨在确定 CICR 的 Ca2+ 敏感性是否降低；表面膜与SR的外围耦合是否成熟； CICR增益是否降低。目标 3 将检验新假设，即两种机制之一会削弱嵴顶消融后胚胎心室收缩装置产生的力。将确定跨桥功能是否正常，但并联弹性（吸收跨桥产生的大部分功）是否增加；或过桥功能是否异常。这些研究的结果将提供新的信息，从而改善先天性心脏病婴儿的护理和治疗。