The adult heart is composed of three concentric layers of cells, the inner endocardial lining, the muscular myocardium, and the outer epicardium. Understanding the embryonic origins and patterning of these three cardiac layers is crucial for our understanding of cardiac development, congenital heart disease, and response to cardiac injury in adults. The origin and developmental patterning of the endocardium and myocardium have been the focus of many studies, while the origins and patterning of epicardium, which develops once the heart tube has undergone cardiac looping, has been poorly explored. Proper development of the epicardium is crucial for maturation of the myocardium and cardiac valves. In addition, the epicardial cells populate and pattern the coronary vessels that are required to oxygenate the heart muscle. In this study, the investigator proposes to examine the molecular and cellular mechanisms regulating the origins and development of the epicardium in zebrafish, as a first step to understanding its role in regulating coronary vessel development. Specifically, she will characterize the origin of the zebrafish epicardium by position, morphology, and gene expression;demonstrate the requirements for tbx5 and tbx18, transcription factors expressed in the epicardial precursors in directing epicardial morphogenesis and maturation by examining loss of function phenotypes;describe the development of the coronary vessels by observing the formation, patterning, maturation, and maintenance of the coronary vessels using a vessel specific GFP transgenic;and delineate the molecular bases of coronary vessel development by examining the development and patterning of the epicardium and coronary vessels in zebrafish mutant (tbx5) predicted, by cross-species analysis, to have epicardium or coronary vessel defects. By capitalizing on the advantages of zebrafish as a model organism, the investigator will illuminate conserved aspects of epicardial and coronary vessel development, as well as delineate a new approach for studying the development of these essential cardiac structures. Future extensions of this project will include the identification of additional molecular and cellular mechanisms that regulate epicardium and coronary vessel development, as well as remodeling after injury. PROJECT
Coronary artery disease affects over 13 million Americans, yet limited treatment options are available due to our limited understanding of coronary artery development and remodeling after injury. Understanding the developmental origins of the coronary arteries is crucial for gaining insight into artery remodeling, as remodeling is often a reactivation of the developmental program. The coronary arteries develop from the epicardium, thus understanding the molecular mechanisms driving the development of the epicardium is a crucial first step to devising treatments for coronary artery disease.
| Singleman, Corinna; Holtzman, Nathalia G (2014) Growth and maturation in the zebrafish, Danio rerio: a staging tool for teaching and research. Zebrafish 11:396-406 |
| Singleman, Corinna; Holtzman, Nathalia G (2012) Analysis of postembryonic heart development and maturation in the zebrafish, Danio rerio. Dev Dyn 241:1993-2004 |
