Grant: Discovery Grants Program - Individual

Being the first organ to form and function, the heart needs to grow and adapt to the changing needs of the organism throughout its life. Cardiac fibroblasts help define the structural and mechanical properties of the heart by secreting and remodeling the extracellular matrix. The differentiation of cardiac fibroblasts is tuned to respond to mechanical load, however, we have a limited understanding of the molecular mechanism responsible for this effect. Our research program will examine the role of the vitamin A metabolite, retinoic acid, in the mechano-transduction pathways that influence the development of cardiac fibroblasts. Retinoic acid, a ligand of nuclear hormone receptors, controls gene expression, and is an important signaling molecule in guiding heart development. During late gestation, retinoic acid synthesis is confined to the epicardium, a mesothelial layer that covers the heart. Our recent studies demonstrate that epicardial retinoic acid signaling plays critical roles in controlling coronary vascular development and the formation of vascular smooth muscle and fibroblast precursor cells. Preliminary studies also suggest that epicardial retinoic acid signaling is influenced by mechanical stress via the conserved Yap/Taz pathway. Our studies will test the novel hypothesis, that retinoic acid signaling controls cardiac fibroblast differentiation in response to mechanical stress. Through in vivo imaging of avian embryonic models, we will first establish the dynamics and patterns of activation of Yap/Taz signaling during epicardial development. Using avian embryos and cell culture models we will next examine the effect of mechanical stress on the activation of Yap/Taz and retinoic acid-signaling in epicardial cells. We will extend these findings to determine the role of retinoic acid signaling in the development of cardiac fibroblasts using embryonic rodent models of altered levels of retinoic acid previously established by our lab. The studies proposed will provide an understanding of a fundamental process that governs the mechanical properties of the developing heart and will provide a new direction to promote our overarching goal of defining the role of vitamin A, and other diet-derived bioactive metabolites in guiding embryonic development.