COLLAGENS OF CARTILAGE AND THE INTERVERTEBRAL DISC

软骨和椎间盘的胶原蛋白

• 批准号: 2909785
• 负责人: David R Eyre
• 金额: $ 25.24万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 1986
• 资助国家: 美国
• 起止时间: 1986-01-01 至 2003-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2909785
• 关键词: active sites; cartilage; chondrocytes; collagen; crosslink; extracellular matrix; fibrous protein; high performance liquid chromatography; human tissue; intermolecular interaction; intervertebral disk; laboratory rabbit; molecular pathology; osteoarthritis; polymerization; protein sequence; protein structure function; proteolysis; stromelysin; tissue /cell culture

This project is using advanced methods in protein chemistry to understand the polymeric architecture and interactions of the various molecular types of collagen that form the framework of cartilage and intervertebral disc tissue. The long-term objective is to define how the various kinds of collagenous protein are organized in the matrix, to what degree they are designed to self-assemble and interact with each other and with other matrix macromolecules in order to form the heteropolymeric fibrillar network. The need for molecular differences in the matrix architecture of different forms of cartilage and between regions within a single tissue, including junction domains with adjacent non-cartilaginous tissues, and the role of different collagen chemistries and modifying molecules are of particular interest. Two tissues, articular cartilage and intervertebral disc, will be studied in greatest detail using bovine and human sources. A focal topic is the manner of covalent intermolecular cross-linking and the scope of heterotypic polymerization in and between the collagen sub-families of molecules. Specific aims include defining precisely the molecular sites and chemistry of covalent interaction between types IX and II collagens, studying the incidence of cross- linking between types I and II collagens, defining the cross-linking mechanisms among the chain isotypes of the collagen V/XI sub-family of gene products, understanding the action of stromelysin and other extracellular proteases in degrading the cartilage collagen network and discovering the mechanism of cross-linking in type X collagen. The latest techniques in protein chemistry will be the primary approach, including HPLC peptide separations, gas-phase automated amino acid sequencing, specialized methods to detect and quantify the unique collagen cross- linking amino acids, and use of specific antibodies. The clinical significance of this work is in providing a molecular basis for understanding the processes whereby articular cartilage is degraded in osteoarthritic joints (osteoarthritis) and intervertebral discs break down with increasing adult age and contribute to common spinal disorders (low back pain). In both tissues a failure of the collagen framework is a central irreversible feature of the cartilage tissue degeneration. There is reason to believe that there may be common mechanisms of tissue destruction in joint cartilages and discs.

该项目正在使用蛋白质化学的先进方法来理解 聚合物结构和各种分子的相互作用 形成软骨和椎间框架的胶原蛋白类型 椎间盘组织。长期目标是定义各种类型如何 胶原蛋白在基质中组织的程度如何 被设计用于自组装和相互之间以及相互之间的相互作用 基质大分子以形成杂聚原纤维 网络。基质结构中分子差异的需要 不同形式的软骨以及单个区域之间的软骨 组织，包括与相邻非软骨的连接域 组织，以及不同胶原化学和修饰的作用 分子特别令人感兴趣。两种组织，关节软骨 和椎间盘，将使用牛进行最详细的研究 和人力资源。一个焦点话题是共价分子间的方式 交联和异型聚合的范围 胶原蛋白分子亚族。具体目标包括定义 精确地确定共价相互作用的分子位点和化学性质 IX 型和 II 型胶原蛋白之间，研究交叉的发生率 I 型和 II 型胶原蛋白之间的连接，定义交联 胶原蛋白 V/XI 亚家族链同种型之间的机制 基因产物，了解溶基质素和其他物质的作用 细胞外蛋白酶降解软骨胶原网络和 发现 X 型胶原蛋白的交联机制。最新的 蛋白质化学技术将是主要方法，包括 HPLC 肽分离、气相自动氨基酸测序、 检测和量化独特的胶原蛋白交叉的专门方法 连接氨基酸，以及使用特异性抗体。 这项工作的临床意义在于提供了分子基础 用于了解关节软骨退化的过程 骨关节炎（骨关节炎）和椎间盘断裂 随着成年年龄的增加而下降，并导致常见的脊柱疾病 （腰背疼痛）。在这两种组织中，胶原蛋白框架的失败是 软骨组织退化的一个不可逆转的主要特征。 有理由相信组织可能存在共同的机制 关节软骨和椎间盘的破坏。