DDR2, a Novel Collagen Receptor, and Mineralization

DDR2，一种新型胶原蛋白受体和矿化

• 批准号: 6924165
• 负责人: WAGNER R DUARTE
• 金额: $ 21.9万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-04-01 至 2007-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6924165
• 关键词: DDR2; Novel; Collagen; Receptor; Mineralization

DESCRIPTION (provided by applicant): Fibrillar type I collagen is the major framework in most mineralized tissues in vertebrates. Its structural role in mineralization is well recognized but its potential role as a ligand to control matrix organization/mineralization is essentially unknown. Discoidin domain receptor 2 (DDR2) is a newly identified fibrillar collagen receptor found in several tissues and organs, however, its presence and roles in mineralized tissues are unknown. Our preliminary studies indicate that DDR2 is highly expressed by osteoblastic cells and that its inhibition leads to severely affected collagen matrix organization/mineralization and altered expression of type I collagen and related MMPs (i.e. rodent interstitial collagenase and gelatinase). Our hypothesis is that signaling through DDR2 in osteoblastic cells modulates collagen matrix organization and mineralization by regulating the level of collagen synthesis and degradation. To test this hypothesis, we propose: 1. To investigate the effects of lowered DDR2 expression in MC3T3-E1 cells on matrix organization and mineralization.1 a. To establish single-cell derived clones expressing lower levels of DDR2. 1b. To evaluate the mRNA expression levels of COLI and interstitial collagen-associated MMPs (MMP2, 13).1c. To characterize the content, maturation, organization and mineralization pattern of collagen matrix produced by these clones; 2. To investigate the effects of overexpression of DDR2 in MC3T3-E1 cells on matrix organization and mineralization. 2a. To establish single-cell derived clones expressing higher levels of DDR2. 2b. To evaluate the mRNA expression levels of COLI and interstitial collagen-associated MMPs (MMP2, 13). 2c. To characterize the content, maturation, organization and mineralization pattern of collagen matrix produced by these clones; 3. To investigate the activation of COLI (alpha1) and MMP2 promoters through DDR2 signaling. The results of this research would provide insights into novel regulatory roles of this newly identified collagen receptor, DDR2, in bone physiology.

描述（由申请人提供）：I型胶原纤维是脊椎动物大多数矿化组织的主要骨架。其在矿化中的结构作用是公认的，但其作为控制基质组织/矿化的配体的潜在作用基本上是未知的。盘状结构域受体2（DDR2）是一种新发现的存在于多种组织和器官中的纤维状胶原受体，但其在矿化组织中的存在和作用尚不清楚。我们的初步研究表明，DDR2由成骨细胞高度表达，并且其抑制导致严重影响胶原基质组织/矿化以及I型胶原和相关MMP（即啮齿动物间质胶原酶和明胶酶）的表达改变。我们假设成骨细胞中通过DDR2的信号传导通过调节胶原合成和降解水平来调节胶原基质的组织和矿化。为了验证这一假设，我们建议： 1.研究MC 3 T3-E1细胞中DDR2表达降低对基质组织化和矿化的影响。建立表达较低水平DDR2的单细胞衍生克隆。1b.评估COLI和间质胶原相关MMPs（MMP 2，13）的mRNA表达水平。表征这些克隆产生的胶原基质的含量、成熟度、组织和矿化模式; 2.探讨DDR2过表达对MC 3 T3-E1细胞基质结构和矿化的影响。2a.建立表达更高水平的DDR2的单细胞衍生克隆。2b.评估COLI和间质胶原相关MMPs（MMP 2，13）的mRNA表达水平。2c.表征这些克隆产生的胶原基质的含量、成熟度、组织和矿化模式; 3.研究COLI（α 1）和MMP 2启动子通过DDR2信号转导的激活。这项研究的结果将为这种新发现的胶原蛋白受体DDR2在骨生理学中的新调节作用提供见解。