TGF beta and coronary vessel development

预定形成冠状血管的细胞在迁移到发育中的心管前心外膜器官(PEO)中。这些细胞在心脏上形成一层上皮层，经历上皮-间充质转化，随后迁移到心脏，随后形成血管。同样，神经脊细胞向心脏的迁移是正常心脏发生所必需的，包括冠状动脉构型和流出道的分隔。我们已经证明，III型TGFb受体(TBRIII)是房室垫上皮-间充质转化和间充质细胞迁移所必需的。我们将检验所有假设，即TBRIII是上皮-间充质迁移的中介物。我们将在鸡中使用实验胚胎学方法，在小鼠中使用遗传学方法，以全面了解TBRIII在这些事件中的作用，因为它们与冠状动脉发育有关。雏鸡的初步数据表明，TBRIII在迁移的神经脊细胞和PEO细胞中都有表达。此外，在体外培养实验中，抗TBRIII抗血清可抑制神经脊细胞的迁移。我们提出的实验将确定TBRIII在冠状动脉血管形成中的作用。确定哪些TGFb信号转导复合体介导细胞转化和细胞迁移将使我们对TGFb信号转导有全面的了解。冠状动脉疾病是人类死亡的主要原因。对冠状动脉血管发育的更清楚的了解可能会发现治疗冠状动脉疾病的新方法。

Cells destined to form the coronary vessels reside in the pro-epicardial organ (PEO) prior to migrating toe the developing heart tube. These cells form an epithelial layer over the heart and undergo epithelial- mesenchymal transformation and subsequent migration into the heart, followed by vessel formation. Similarly, the migration of neural crest cells into the heart is required for proper cardiogenesis, including coronary artery patterning and the septation of the outflow tract. We have shown that the Type III TGFb receptor (TBRIII) is required for epithelial- mesenchymal transformation and mesenchymal cell migration in the atrioventricular (AV) cushion of the heart. We will test the overall hypotheses that TBRIII is a mediator of epithelial-mesenchymal migration. We will use experimental embryological approaches in chick and genetic approaches in the mouse to gain a comprehensive understanding of the role of TBRIII in these events as they relate to coronary vessel development. Preliminary data in the chick demonstrate that TBRIII is expressed by both migrating neural crest cells and cells of the PEO. In addition, anti-TBRIII antisera inhibits the migration of neural crest cells in in vitro explant assays. The experiments we propose will determine the function of TBRIII in coronary vessel formation. The determination of which TGFb signal transduction complexes mediate cell transformation and cell migration will give general insight into TGFb signal transduction. Coronary vessel disease is a major cause of death in humans. A clearer understanding of coronary vessel development may identify novel approaches to treating coronary disease.