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Collagen assembly: from molecules to fibrils

胶原蛋白组装：从分子到原纤维

基本信息

批准号：
EP/R011818/1
负责人：
Andela Saric
金额：
$ 12.84万
依托单位：
University College London
依托单位国家：
英国
项目类别：
Research Grant
财政年份：
2018
资助国家：
英国
起止时间：
2018 至无数据
项目状态：
已结题

来源：
https://gtr.ukri.org/projects?ref=EP%2FR011818%2F1
关键词：
Collagen assembly molecules fibrils

项目摘要

One of the most remarkable examples of self-assembly in living organisms is the formation of collagen architectures. Collagen is the most abundant protein in the animal kingdom, where its molecules robustly self-associate into micron-sized fibrils of well defined morphologies. These fibrils form the structural basis of mammalian connective tissues and, as the major component of the extracellular matrix, are crucial for the determination of cell phenotype, cell adhesion, and tissue regulation and signalling. For the same reasons the process of collagen assembly is also at the centre of engineering efforts to design functional biomimetic materials and platforms for cell and tissue manipulation. However, the current understanding of the physical processes that drive collagen assembly from molecules to micron-sized fibrils, and the determinants of the resulting morphologies, is far from complete. The goals of this project are to bridge molecular and microscopic scales of the dynamic process of collagen assembly, and identify the physical principles of the assembly of collagen and collagen-mimetic molecules. This will be achieved by developing a minimal physical model of collagen-like molecules, implemented in a molecular dynamics framework. Because of its simplicity, such a physical model can reach experimentally relevant time- and length-scales of the assembly, and its results can be directly compared with experiments of our collaborators. Two specific objectives are to: 1) Map the design of small collagen-mimetic molecules on the resulting fibrillar architectures, and hierarchical pathways of fibril nucleation and growth. 2) Investigate the influence of the molecular charge patterns and hydrophobic interactions on the self-assembly of native collagen molecules. The long-term goals are to understand the physical principles behind robust collagen assembly in nature, as well as the roots of its failure in pathological processes, and to provide guidelines for the rational design of collagen-mimetic materials. The results from this project will give insights into the roots of collagen remodelling in diseases and ageing, and guide the design of collagen scaffolds for biotechnological applications.

生物体中自组装最显著的例子之一是胶原蛋白结构的形成。胶原蛋白是动物界中最丰富的蛋白质，其分子强烈地自缔合成具有明确形态的微米级原纤维。这些原纤维形成哺乳动物结缔组织的结构基础，并且作为细胞外基质的主要组分，对于确定细胞表型、细胞粘附以及组织调节和信号传导至关重要。出于同样的原因，胶原蛋白组装的过程也是工程努力的中心，以设计用于细胞和组织操作的功能仿生材料和平台。然而，目前的理解，驱动胶原蛋白组装从分子到微米级的原纤维的物理过程，以及由此产生的形态的决定因素，是远远不够的。本项目的目标是在胶原蛋白组装的动态过程的分子和微观尺度上架起桥梁，并确定胶原蛋白和胶原蛋白模拟分子组装的物理原理。这将通过开发胶原蛋白样分子的最小物理模型来实现，在分子动力学框架中实现。由于其简单性，这样的物理模型可以达到实验相关的时间和长度尺度的组装，其结果可以直接与我们的合作者的实验进行比较。两个具体目标是：1）在所得的原纤维结构上映射小胶原蛋白模拟分子的设计，以及原纤维成核和生长的分级途径。2)研究分子电荷模式和疏水相互作用对天然胶原分子自组装的影响。长期目标是了解自然界中强大的胶原蛋白组装背后的物理原理，以及其在病理过程中失败的根源，并为胶原蛋白模拟材料的合理设计提供指导。该项目的结果将深入了解疾病和衰老中胶原蛋白重塑的根源，并指导生物技术应用中胶原蛋白支架的设计。