Fetal alcohol spectrum disorder (FASD) birth defects include cardiac atrial, ventricular, atrioventricular septal defects, and conotruncal defects. The long-term goal of this work is to elucidate the mechanisms of ethanol induced cardiac defects, particularly septal defects, and folic acid protection of these defects. Cardiac tissues are derive from distinct progenitor populations: first heart field (FHF) and second heart field (SHF). FHF lineage contributes to both chambers. SHF progenitors contribute to most of the myocardium and outflow tract (OFT). Interfering with any of these progenitor populations could cause defects in chambers and valves. These progenitors originate in different locations from the embryonic mesoderm by controlled regulation of different signaling molecules. Interaction between specific cardiac transcription factors and chromatin remodeling complex BAF controls heart development by regulating cardiac gene expression. Cardiac regulatory networks are conserved across vertebrate species, from zebrafish to human. Initial studies showed that zebrafish embryos exposed to ethanol during distinct cardiogenic events disrupt cardiac specification, chamber and valve development morphogenesis. Folic acid (FA) supplementation rescued ethanol induced developmental defects, including valve development defects. There is a significant gap in our knowledge of ethanol effects on cardiac regulatory networks, progenitor populations and valve morphogenesis mechanisms in FASD patients. Our overall hypothesis is that ethanol induces fluctuation in expression of cardiac transcription factors and BAF chromatin remodeling complex components, alters FHF and SHF progenitor contributions to the heart causing chamber and valve development defects, and folic acid, which affects epigenetic processes, will restore a more normal balance of gene expression levels, restoring more normal cardiogenesis. Our experimental plan to dissect the cellular and molecular mechanisms underlying cardiac defects in our zebrafish model of FASD specifically addresses priorities described in PA-12-232: Stem Cells and Alcohol-induced Tissue Injuries, which targets 'fetal alcohol syndrome', 'cardiovascular disease'and 'improving animal models for alcohol research', particularly alcohol effects on specific stem/progenitor cells. We propose the following specific aims for this project.
Specific Aim 1. Examine ethanol effects on regulators of myocardial progenitors and determine the contribution of FHF and SHF derived cells to ethanol induced cardiac defects.
Specific Aim 2. Molecular and cellular characterization of ethanol induced atrioventricular canal and valve development defects. Proposed studies will help identify ethanol sensitive morphogenesis mechanisms that may contribute to heart defects in FASD patients. This project will dissect ethanol sensitive cellular and molecular cardiogenesis mechanisms, providing insight into congenital heart defect genesis and FA's protective role.
Fetal alcohol spectrum disorder (FASD) is the most frequent preventable birth defect, which includes heart defects. Congenital heart defects occur in about half of FASD patients, producing significant societal costs (financial, morbidity and mortality). There is a significant gap in our knowledge of alcohol effects on heart morphogenesis cellular and molecular mechanisms in FASD patients, and our experimental plan to dissect the cellular and molecular mechanisms underlying cardiac defects in our zebrafish model of FASD specifically addresses priorities described in PA-12-232: Stem Cells and Alcohol-induced Tissue Injuries, which targets 'fetal alcohol syndrome', 'cardiovascular disease'and 'improving animal models for alcohol research', particularly alcohol effects on specific stem/progenitor cells.
|Sarmah, Swapnalee; Muralidharan, Pooja; Marrs, James A (2016) Embryonic Ethanol Exposure Dysregulates BMP and Notch Signaling, Leading to Persistent Atrio-Ventricular Valve Defects in Zebrafish. PLoS One 11:e0161205|
|Muralidharan, Pooja; Sarmah, Swapnalee; Marrs, James A (2015) Zebrafish retinal defects induced by ethanol exposure are rescued by retinoic acid and folic acid supplement. Alcohol 49:149-63|