胶原蛋白甘氨酸突变导致成骨不全症的分子机制研究

项目名称： 胶原蛋白甘氨酸突变导致成骨不全症的分子机制研究

项目编号： No.21305056

项目类型： 青年科学基金项目

立项/批准年度： 2014

项目学科： 数理科学和化学

项目作者： 肖建喜

作者单位： 兰州大学

项目金额： 25万元

中文摘要： 作为人体中含量最丰富的蛋白质，胶原蛋白扮演着重要的双重角色。一方面它作为结构蛋白, 为皮肤、骨骼、软骨和血管壁提供抗拉强度；另一方面,它具有高度生物活性。I型胶原蛋白具有特征性的（Gly-X-Y）n重复序列和三重螺旋结构，即使一个单一的甘氨酸突变也会导致成骨不全症（OI）。成骨不全症的表型差异很大，变化范围从轻度的骨质脆弱，到围产期致死病例；然而，成骨不全症的表型和胶原蛋白基因型之间的关系尚不清楚。本项目我们通过对胶原蛋白Gly突变的生物信息学，NMR和CD方法的整合研究，从序列，结构，动力学，稳定性以及功能等多个层面，全面解析成骨不全症的分子机制，重点阐明有代表性的Gly-Ser，Gly-Arg以及整合素结合位点附近的OI突变被其邻近序列调控表型严重程度的作用机制，有助于开发新的成骨不全症基因诊断和治疗的方法。

中文关键词： 胶原蛋白；核磁共振；荧光；圆二色谱；成骨不全症

英文摘要： Collagen, the single most abundant protein in the human body，plays a critical dual role. As a structural protein, it provides tensile strength to skin, bone, tendon and ligament; In addition, it is also highly bioactive.Type I collagen contains the characteristic (Gly-X-Y)n sequence pattern and triple helix structure. Even a single Gly mutation in Type I collagen leads to Osteogenesis Imperfecta(OI).The severities of OI vary in a wide range from mild cases with multiple fractures to perinatal lethal cases. The relationship of genotypes and phenotypes of OI is not well understood. Here we apply an integrated approach of Bioinformatics, NMR and CD to investigate the Gly substitutions in collagen at multiple levels including sequence, structure, dynamics, stability and function. Bioinformatics analysis of Gly-X mutations in Type I collagen will be performed to investigate the genotype/phenotype relationship of OI,while NMR and CD are ideally suited to elucidate the structural and dynamic bases of OI.In order to systematically decipher the molecular mechanism of OI, we will explore the effects of Gly substitutions by Ser and Arg as well as Gly substitutions near the integrin binding site. Understanding the role of the residues nearby a Gly mutation on the phenotypes of OI,will help develop novel diagnostic and thera

英文关键词： Collagen；NMR；Fluorescence；CD；Osteogenesis Imperfecta