Role of Discoidin Domain Receptor 2 in Valvulogenesis

盘状结构域受体 2 在瓣膜形成中的作用

• 批准号: 7195768
• 负责人: EDIE C GOLDSMITH
• 金额: $ 32.69万
• 依托单位: UNIVERSITY OF SOUTH CAROLINA AT COLUMBIA
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-04-01 至 2010-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7195768
• 关键词: Address; Binding; Biochemical; Cardiac; Cell Differentiation process; Cell physiology; Cells; Class; Collagen; Collagen Receptors; Congenital Heart Defects; DDR1 gene; Data; Defect; Deposition; Development; Enzymes; Equilibrium; Extracellular Matrix; Extracellular Matrix Proteins; Fibrillar Collagen; Fibroblasts; Heart; Invaded; Matrix Metalloproteinases; Mediating; Mesenchymal; Mesenchyme; Molecular; Nature; Phosphorylation; Play; Process; Production; Protein Family; Proteins; Receptor Protein-Tyrosine Kinases; Research; Role; Signal Transduction; Testing; Translating; density; design; discoidin domain receptor 2; discoidin receptor; malformation; member; novel; receptor; response

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.

描述（由申请人提供）：瓣膜形成开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，最终产生填充有成纤维细胞的瓣膜小叶。由瓣膜畸形引起的缺陷是所有先天性心脏缺陷中最常见的，这强调了研究可能调节瓣膜正常发育的分子的必要性。瓣膜形成过程的核心是胶原蛋白在垫子和小叶内的沉积和重塑。最近，一类新型受体酪氨酸激酶，盘状蛋白结构域受体（DDR），已被证明可以特异性结合胶原蛋白并增加参与胶原蛋白重塑的酶的表达。虽然该蛋白质家族有两个成员：DDR1 和 DDR2，但已在间充质细胞和成纤维细胞（心脏内产生胶原蛋白的细胞）上检测到 DDR2。本文提供的初步数据证明了 DDR2 在形成细胞侵入垫子和在瓣膜内产生胶原蛋白所需的迁移间充质细胞中的作用。 DDR2 与胶原蛋白相互作用的性质以及该受体上调参与胶原蛋白重塑的蛋白质的能力导致了这样的假设：DDR2 和胶原蛋白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 信号传导的关键决定因素。此外，不同组织状态下DDR2与胶原蛋白的相互作用可调节受体分布并调节间充质细胞功能。设计了以下具体目标来检验这一假设：1）确定 DDR2 在 EMT 和早期瓣膜形成过程中介导细胞侵袭和 ECM 重塑中的作用； 2) 确定胶原密度和组织对发育瓣膜中 DDR2 激活的影响； 3) 表征 DDR2 和胶原蛋白之间发生的分子相互作用。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了解该受体如何感知发育瓣膜内胶原蛋白组织和分布中发生的变化，以及这些变化如何最终转化为细胞功能。