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.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
5P01HL036059-16
Application #
6589566
Study Section
Project Start
2002-04-01
Project End
2003-03-31
Budget Start
Budget End
Support Year
16
Fiscal Year
2002
Total Cost
Indirect Cost
Name
Medical College of Georgia (MCG)
Department
Type
DUNS #
City
Augusta
State
GA
Country
United States
Zip Code
30912
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