Transcriptional control of cardiac fibroblast development

作为第一个形成和发挥功能的器官，心脏需要在其一生中不断生长和适应机体不断变化的需求。心脏成纤维细胞通过分泌和重塑细胞外基质来帮助定义心脏的结构和机械特性。心脏成纤维细胞的分化被调节以响应机械负荷，然而，我们对这种效应的分子机制的理解有限。我们的研究计划将研究维生素A代谢产物视黄酸在影响心脏成纤维细胞发育的机械转导途径中的作用。视黄酸是核激素受体的配体，控制基因表达，是指导心脏发育的重要信号分子。在妊娠晚期，视黄酸的合成仅限于心外膜，即覆盖心脏的间皮层。我们最近的研究表明，心外膜维甲酸信号在控制冠状动脉血管发育和血管平滑肌和成纤维细胞前体细胞的形成中起着关键作用。初步研究还表明，心外膜视黄酸信号通过保守的雅普/Taz通路受到机械应力的影响。我们的研究将测试新的假设，即视黄酸信号控制心脏成纤维细胞分化的机械应力。通过对禽类胚胎模型的体内成像，我们将首先建立心外膜发育过程中雅普/Taz信号转导的激活动力学和模式。使用禽类胚胎和细胞培养模型，我们接下来将研究机械应力对心外膜细胞中雅普/Taz和视黄酸信号传导的激活的影响。我们将扩展这些发现，以确定维甲酸信号在心脏成纤维细胞的发展中的作用，使用我们实验室先前建立的维甲酸水平改变的胚胎啮齿动物模型。提出的研究将提供对控制发育中心脏机械特性的基本过程的理解，并将提供一个新的方向，以促进我们的总体目标，即定义维生素A和其他饮食衍生的生物活性代谢物在指导胚胎发育中的作用。

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.