Role of Discoidin Domain Receptor 2 in Valvulogenesis

描述（由申请人提供）：瓣膜形成开始于无细胞基质填充的心垫，随后被产生胶原的间充质细胞侵入，最终形成成纤维细胞填充的瓣膜小叶。由瓣膜畸形引起的缺陷是所有先天性心脏缺陷中最普遍的，这强调了研究可能调节瓣膜发育的分子的必要性。瓣膜形成过程的核心是在软垫和小叶内胶原蛋白的沉积和重塑。最近，一类新的酪氨酸激酶受体，盘状蛋白结构域受体（DDR），已被证明可以特异性结合胶原并增加参与胶原重塑的酶的表达。虽然该蛋白家族有两个成员，DDR1和DDR2，但在心脏内的间充质细胞和成纤维细胞（胶原蛋白的产生细胞）中检测到DDR2。本文提出的初步数据表明，DDR2在迁移间充质细胞的形成中发挥了作用，这是细胞侵入软垫和瓣膜内胶原蛋白产生所必需的。DDR2与胶原相互作用的性质以及该受体上调参与胶原重塑的蛋白的能力导致了这样的假设，即DDR2和胶原之间的相互作用是瓣膜形成过程中瓣膜间充质细胞分化和ECM信号传导的关键决定因素。此外，DDR2与不同组织状态下的胶原蛋白的相互作用调节了受体的分布并调节了间充质细胞的功能。以下具体目标已被设计来验证这一假设：1)确定DDR2在EMT和早期瓣膜形成期间介导细胞入侵和ECM重塑中的作用；2)测定胶原密度和组织对瓣膜发育过程中DDR2活化的影响；3)表征DDR2与胶原蛋白之间的分子相互作用。控制DDR2与胶原蛋白相互作用的物理和分子参数的表征将有助于我们理解这种受体如何感知胶原蛋白组织和分布在发育中的瓣膜中发生的变化，以及这些变化最终如何转化为细胞功能。

DESCRIPTION (provided by applicant): Valvulogenesis begins with acellular matrix filled cardiac cushions that are subsequently invaded by collagen producing mesenchymal cells that ultimately give rise to fibroblasts populated valve leaflets. Defects arising from malformations of the valves are the most prevalent of all congenital heart defects underscoring the need to investigate molecules that may regulate proper valve development. Central to the process of valve formation is the deposition and remodeling of collagen within the cushions and leaflets. Recently, a novel class of receptor tyrosine kinases, the discoidin domain receptors (DDR), have been demonstrated to specifically bind collagen and increase expression of enzymes involved in collagen remodeling. While there are two members of the protein family, DDR1 and DDR2, DDR2 has been detected on mesenchymal cells and fibroblast, the collagen producing cells within the heart. Preliminary data presented herein demonstrates a role for DDR2 in the formation of the migrating mesenchymal cells required for cellular invasion of the cushions and the production of collagen within the valves. The nature of the interaction of DDR2 with collagen and the ability of this receptor to up-regulate proteins involved in collagen remodeling has led to the hypothesis that interactions between DDR2 and collagen are critical determinants in valve mesenchymal cell differentiation and ECM signaling during valve formation. Furthermore, that the interaction of DDR2 with collagen in different organizational states regulates receptor distribution and modulates mesenchymal cell function. The following specific aims have been designed to test this hypothesis: 1) to determine the role of DDR2 in mediating cellular invasion and ECM remodeling during EMT and early valve formation; 2) to determine the effect of collagen density and organization on DDR2 activation in developing valves; and 3) to characterize the molecular interactions occurring between DDR2 and collagen. The characterization of the physical and molecular parameters that govern the interaction of DDR2 with collagen will aid in our understanding of how this receptor perceives changes occurring in collagen organization and distribution within the developing valves and how these changes are ultimately translated into cellular functions.