Biomolecular Mechanics of Collagen Monomers And Fibrils

胶原单体和原纤维的生物分子力学

• 批准号: 6620506
• 负责人: CHARLOTTE L PHILLIPS
• 金额: $ 16.09万
• 依托单位: UNIVERSITY OF MISSOURI-COLUMBIA
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-03-08 至 2005-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6620506
• 关键词: animal tissue; aorta; atomic force microscopy; biomechanics; cell components; collagen; connective tissue; covalent bond; crosslink; disease /disorder model; extracellular matrix; gene mutation; intermolecular interaction; monomer; osteogenesis imperfecta; protein protein interaction; protein structure function; skin; tendons; tensile strength

DESCRIPTION (provided by applicant): Biomechanical stability and strength of connective tissues have long been attributed to covalent intermolecular crosslinks between collagen monomers. Type I collagen, a major component of bone, tendon, skin, and the vasculature, is normally heterotrimeric, consisting of two al (I) chains and a single a2(I) chain, [al(I)2a2(I)]. However, type I collagen in oim mice is exclusively composed of al(I) homotrimers, [al(I)3] (result of a null mutation in the a2(I) gene). Oim mice are a superb model system for examining the functional necessity of the a2(I) chain. We hypothesize that the absence of a2(I) chains perturbs collagen fibril formation, collagen-collagen interactions, and intra- and inter-molecular crosslinking, compromising the structural and biomechanical integrity of connective tissues. In vivo studies using oim mice demonstrate that the presence of type I collagen homotrimers significantly decreases the biomechanical integrity of bone, tendon, skin and aorta. Further analyses using oim mice suggest non-covalent collagen intra- and intermolecular interactions and organization maybe the critical factors regulating mechanical integrity rather than collagen crosslinking. These results question the dogma that covalent intermolecular crosslinks between collagen monomers are the principal determinants of stability and biomechanical integrity of the fibrillar architecture, and compel us to consider other forces and interactions, such as the inherent mechanical properties of individual collagen monomers and non-covalent protein-protein interactions. Recent advances in the application of atomic force microscopy now make it possible to analyze inherent mechanical properties of single biomolecules and molecule-molecule interactions. We propose to use atomic force microscopy to define the role of a2(I) chains 1) in the inherent mechanical integrity of collagen monomers, 2) in non-covalent collagen-collagen interactions, and 3) in the inherent mechanical integrity of collagen fibrils, as well as provide a powerful new tool for defining and understanding the pathogenesis of fibrillar collagen mutations and other extracellular matrix components and their role in connective tissue disease.

描述（由申请人提供）：生物力学稳定性和强度 结缔组织长期以来一直归因于共价分子 胶原蛋白单体之间的交联。 I型胶原蛋白，是 骨骼，肌腱，皮肤和脉管系统通常是异三聚体，组成 在两个Al（i）链和一个A2（i）链中，[al（i）2a2（i）]。但是，类型i OIM小鼠中的胶原蛋白专门由Al（i）同构体组成，[al（i）3] （A2（i）基因中无效突变的结果）。 OIM小鼠是一款出色的模型 检查A2（i）链的功能必要性的系统。我们 假设缺乏A2（i）链条 形成，胶原 - 胶原蛋白相互作用以及分子间和分子间 交联，损害结构和生物力学完整性 结缔组织。使用OIM小鼠的体内研究表明 I型胶原蛋白同二聚体的存在显着降低 骨，肌腱，皮肤和主动脉的生物力学完整性。进一步分析 OIM小鼠建议非共价胶原蛋白内和分子间相互作用 组织也许是调节机械完整性的关键因素 而不是胶原蛋白交联。这些结果质疑教条 胶原蛋白单体之间的共价分子交联是主要的 原纤维的稳定性和生物力学完整性的决定因素 建筑，并迫使我们考虑其他力量和互动，例如 单个胶原蛋白单体和 非共价蛋白质 - 蛋白质相互作用。应用程序的最新进展 现在，原子力显微镜可以分析固有的机械 单个生物分子和分子 - 分子相互作用的特性。我们 建议使用原子力显微镜来定义A2（i）链的作用1） 胶原蛋白单体的固有机械完整性，2）非共价 胶原 - 胶原蛋白相互作用，3）在固有的机械完整性中 胶原原纤维，并为定义和 了解原纤维胶原突变和其他的发病机理 细胞外基质成分及其在结缔组织疾病中的作用。