Congenital heart disease is the leading cause of death in the western world affecting approximately 1.3 million Americans. The heart initially forms in vertebrates as a bilaminar tube comprised of an inner endocardium and outer myocardial layer. At later stages of development a third layer is added to the heart from the epicardium which forms from a dynamic precursor structure, the proepicardial organ (PEO) which forms on the septum transversum, a structure adjacent to the heart. As the embryo matures, cells from the PEO migrate onto the heart surface ultimately giving rise to several essential cell types in the adult heart including cardiac fibroblasts and the smooth muscle cells of the vasculature.
The aim of this proposal will leverage our series of unique technologies, reagents, and animal models to elucidate the molecular and cellular pathways required for the formation and function of the epicardium. In doing so, we will provide a platform for studying heart formation and hemostasis, and thus proved mechanistic insight into human congenital heart disease.
Congenital malformations, or structural birth defects, are now the leading cause of infant mortality in the US. Of the congenital malformations, congenital heart disease (CHD) is the most common. Critical to normal development and congenital heart disease is the epicardium, a structure that gives rise to essential cell types in the developing and adult heart. We have recently developed genetic and biochemical approaches that enable the interrogation of the molecular pathways involved in epicardial formation and function. Thus, our approach will provide mechanistic insight into the cause and ultimately treatment of CHD.
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