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.
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