Biomolecular Mechanics of Collagen Monomers And Fibrils

描述（由申请人提供）：生物力学稳定性和强度 结缔组织长期以来被认为是共价分子间的 胶原单体之间的交联。I型胶原蛋白， 骨、肌腱、皮肤和脉管系统通常是异三聚体， 两个α 1（I）链和一个α 2（I）链，[α 1（I）2a 2（I）]。然而，I型 oim小鼠中的胶原仅由al（I）同源三聚体[al（I）3]组成。 （a2（I）基因中的无效突变的结果）。OIM小鼠是一个极好的模型 用于检查α 2（I）链的功能必要性的系统。我们 假设α 2（I）链的缺失扰乱了胶原原纤维 形成，胶原-胶原相互作用，以及分子内和分子间 交联，损害结构和生物力学的完整性， 结缔组织使用oim小鼠的体内研究表明， I型胶原同源三聚体的存在显著降低了 骨、肌腱、皮肤和主动脉的生物力学完整性。进一步分析使用 OIM小鼠提示非共价胶原分子内和分子间相互作用 和组织可能是调节机械完整性的关键因素 而不是胶原蛋白交联。这些结果质疑了 胶原单体之间的共价分子间交联是主要的 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相互作用，例如 单个胶原单体的固有机械性能， 非共价蛋白质相互作用。应用的最新进展 原子力显微镜的发展使我们有可能分析 单个生物分子的性质和分子-分子相互作用。我们 建议使用原子力显微镜来定义α 2（I）链1）在 胶原蛋白单体的固有机械完整性，2）以非共价键 胶原-胶原相互作用，以及3）在固有的机械完整性， 胶原纤维，以及提供了一个强大的新工具， 了解纤维胶原突变的发病机制和其他 细胞外基质成分及其在结缔组织病中的作用。

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.