Normal Cardiac Outflow Tract Development Depends on Retinoic Acid Signaling

Doctor's Name: 
Margaret L. Kirby, Ph.D.
Hospital/Institution: 
Duke University Medical Center

Heart malformations commonly involve incorrect alignment of the aorta with the left ventricle and the associated ventricular defect such that oxygenated blood mixes with deoxygenated blood in the right ventricle. This is a key feature of several congenital heart defects. Excess exposure to Vitamin A or its active derivative called retinoic acid causes this type of defect in humans and animal models. Animal studies have also shown that some retinoic acid is essential for normal development of the heart. However, little is known about the function of retinoic acid in normal development of the heart.

Preliminary data suggests that retinoic acid is essential for controlling the levels of a growth factor called fibroblast growth factor (FGF) 8 in the developing neck or pharyngeal region. The heart also develops in this region at the time that FGF8 is expressed. However, too muchFGF8 signaling disrupts the development of the myocardium that is required for correct alignment of the aorta with the left ventricle. The current studies will test the hypothesis that retinoic is released by a population of cells that migrate into the pharynx, and this retinoic acid suppresses the expression of the FGF8 dampen signaling. The retinoic acid suppression of FGF8 signaling happens at a time that is critical for addition of myocardium to the heart that controls aortic alignment with the left ventricle.

Award Date 1: 
2006
Award Amount 1: 
$88,073
Award Date 2: 
2007
Award Amount 2: 
$90,711