Collagens of Cartilage and the Intervertebral Disc

软骨和椎间盘的胶原蛋白

• 批准号: 7085569
• 负责人: David R Eyre
• 金额: $ 33.68万
• 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 2009-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7085569
• 关键词: aging; alleles; cartilage; clinical research; collagen; crosslink; disease /disorder proneness /risk; extracellular matrix; gene mutation; human tissue; hyaline substance; intervertebral disk; mass spectrometry; molecular assembly /self assembly; molecular pathology; oxidation; protein isoforms; protein protein interaction; protein structure function; spine disorder; tryptophan

DESCRIPTION (provided by applicant): This project is using advanced methods in protein analysis to study the complex polymeric assembly of collagens and associated proteins that frame the extracellular matrix of cartilages. Covalent cross-linking mechanisms that stabilize the network and non-covalent protein-protein interactions that drive the assembly are of particular interest. We aim to understand the mechanism of cross-linking of the type IX collagen molecule onto the type II collagen fibril, and the role in this of type XI collagen, another component of the heterotypic polymer. A molecular model of the collagen IX-collagen 11 interaction is being refined based on the placement of cross-linking residues. The properties of the short variant of the collagen IX molecule used in the intervertebral disc, compared with the long form of hyaline cartilage, are being determined. This includes studying how tryptophan (W)-containing allelic variants (polymorphisms) of two of the collagen IX chains (encoded by COL9A2 and COL9A3) can cause the reported increased risk of disc degeneration associated with these genotypes. Genotyped samples of human cartilage and disc tissue positive for the W-alleles are being analyzed to determine if the expressed collagen IX becomes post-translationally altered such that it could lead to accelerated disc degeneration and/or nerve root irritation. Collagen V and XI gene products and splicing variants expressed in the intervertebral disc are being characterized in terms of number of molecular species represented, for their covalent cross-linking partners in the matrix and N-propeptide domain binding interactions. The binding sites for matrilin-3, a protein that selectively binds to components of the collagen network, are being defined in the collagen subunits. Any additional covalently bonded molecular components of the collagen network will also be identified. The clinical significance of the work is in providing a basis in molecular structure for understanding processes through which articular cartilages and intervertebral discs may be at risk of being degraded during adult life. Since mechanical failure of the collagen framework of both tissues is a key, irreversible feature of age-related joint degeneration, new insights on molecular mechanisms may offer the basis of therapeutic advances.

描述（由申请人提供）：该项目正在使用先进的蛋白质分析方法来研究构成软骨细胞外基质的胶原蛋白和相关蛋白质的复杂聚合组装。稳定网络的共价交联机制和驱动组装的非共价蛋白质-蛋白质相互作用特别令人感兴趣。我们的目的是了解 IX 型胶原蛋白分子与 II 型胶原原纤维交联的机制，以及异型聚合物的另一种成分 XI 型胶原蛋白在其中的作用。胶原蛋白 IX-胶原蛋白 11 相互作用的分子模型正在根据交联残基的位置进行完善。与长形式的透明软骨相比，用于椎间盘的胶原 IX 分子的短变体的特性正在确定。这包括研究两条胶原 IX 链（由 COL9A2 和 COL9A3 编码）的含色氨酸 (W) 等位基因变体（多态性）如何导致与这些基因型相关的椎间盘退变风险增加。正在分析 W 等位基因呈阳性的人类软骨和椎间盘组织的基因分型样本，以确定表达的胶原蛋白 IX 是否会发生翻译后改变，从而导致椎间盘加速退化和/或神经根刺激。椎间盘中表达的胶原蛋白 V 和 XI 基因产物和剪接变体的特征在于所代表的分子种类数量、基质中的共价交联伙伴和 N-前肽结构域结合相互作用。 matrilin-3（一种选择性结合胶原蛋白网络成分的蛋白质）的结合位点在胶原蛋白亚基中被定义。胶原蛋白网络的任何其他共价键合分子成分也将被识别。 这项工作的临床意义在于为理解关节软骨和椎间盘在成年期间可能面临退化风险的过程提供分子结构基础。由于两种组织的胶原蛋白框架的机械失效是与年龄相关的关节退化的一个关键的、不可逆转的特征，因此对分子机制的新见解可能为治疗进展提供基础。