Role of Discoidin Domain Receptor 2 in Valvulogenesis

描述(申请人提供)：瓣膜形成始于充满无细胞基质的心脏垫，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。瓣膜畸形引起的缺陷是所有先天性心脏缺陷中最常见的，这突显了研究可能调节瓣膜正常发育的分子的必要性。瓣膜形成过程的中心是垫层和瓣叶内胶原的沉积和重塑。最近，一类新的受体酪氨酸激酶-盘状结构域受体(DDR)被证明能特异性地结合胶原并增加参与胶原重塑的酶的表达。虽然有两个蛋白质家族的成员，DDR1和DDR2，但已经在心脏内产生胶原的间质细胞和成纤维细胞上检测到DDR2。本文提供的初步数据表明，DDR2在移行间充质细胞的形成中发挥了作用，这些细胞是细胞侵入气垫和在瓣膜内产生胶原所必需的。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一种假说，即DDR2与胶原之间的相互作用是瓣膜间充质细胞分化和瓣膜形成过程中ECM信号转导的关键决定因素。此外，在不同的组织状态下，DDR2与胶原的相互作用调节受体的分布，调节间充质细胞的功能。为了验证这一假说，人们设计了以下特定目标：1)确定DDR2在EMT和瓣膜形成早期介导细胞侵袭和ECM重塑中的作用；2)确定胶原密度和组织对发育中瓣膜DDR2激活的影响；以及3)描述DDR2和胶原之间发生的分子相互作用。对控制DDR2与胶原相互作用的物理和分子参数的表征将有助于我们理解该受体如何感知胶原组织和在发育中的瓣膜内分布的变化，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.