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The mechanics of the collagen fibrillar network in ageing cartilage

老化软骨中胶原纤维网络的力学

基本信息

批准号：
BB/R003610/1
负责人：
Himadri Shikhar Gupta
金额：
$ 50.32万
依托单位：
Queen Mary University of London
依托单位国家：
英国
项目类别：
Research Grant
财政年份：
2017
资助国家：
英国
起止时间：
2017 至无数据
项目状态：
已结题

来源：
https://gtr.ukri.org/projects?ref=BB%2FR003610%2F1
关键词：
mechanics collagen fibrillar network ageing

项目摘要

The connective tissues in our bodies are made up of both cells as well as a fibrous matrix around the cells. The fibrous matrix plays the major role in giving the tissue its mechanical properties needed for function. Despite having very different functions, the fibrous matrices of different soft tissues are at the molecular level made up of similar building blocks: collagen molecules, long sugar chains linked by protein (proteoglycans), and water. In particular, collagen molecules form long thin fibrils, which assemble into a network along with the gel-like material of proteoglycans and water. To achieve a range of diverse functions from the same building blocks, different soft tissues often vary the relative proportion of fibrils to the proteoglycan gel, or their orientation or interconnection to form complex composite materials at very small scales, below the thickness of a human hair. When we age, the properties of our connective tissues tend to deteriorate: e.g. skin becomes stiffer, and cartilage breaks down in osteoarthritis. These adverse changes arise from changes in either the intrinsic properties of the building blocks, or in their architecture. Because these changes occur at very small (nanometre) length scales, it is challenging to find out both the change and its effect on mechanics. To address this, our group has developed a high resolution X-ray imaging technique which works like a diffraction grating for collagen: it picks up regularities in the arrangement of the nanoscale collagen fibril networks in tissues, and when used with a very bright X-ray source like a synchrotron, can track how the fibrils stretch, reorient or otherwise respond to loads. In this project, we will apply this method to understand how the nanoscale mechanics of the collagen fibrillar network in cartilage changes in ageing. Articular cartilage serves as a frictionless bearing surface in joints, and cushions the load transfer between bones. If overloaded, the fibrous matrix breaks down and leads to osteoarthritis, joint pain and immobility. We aim to understand how the compositional changes in collagen link to the alterations in its nanoscale mechanics - and eventually to joint breakdown. We will combine the X-ray technique with high-level characterisation of the protein composition and structure in the tissue as it ages. Such a combination is completely novel: the X-ray technique has not been applied to cartilage before, and its combination with proteomics enables a clear link between structural change and mechanical function.In cartilage, the collagen fibrillar network resists the swelling pressure of the proteoglycan gel. We first aim to understand how this load-balance changes in ageing, and by varying the chemical structure and relative proportion of different components in cartilage, to understand the mechanisms linking changes at the molecular level to disruption of mechanical equilibrium. Secondly, we will study real-time deformation of collagen fibrils as they are subjected to the types of load observed in real life and how ageing affects these dynamics. This is especially relevant because ageing leads to fibrillated and disrupted cartilage, but the mechanism by which collagen fibrils fail to resist loading is not understood. We will then focus on two types of relevant biomechanics: repeated loading or local traumatic impact. First, we will investigate whether the fibrillar response to repetitive loading is altered in ageing. Then, we will map, with micron-resolution, how collagen fibrils around the site of a local injury deform, testing the hypothesis that compositional change in ageing enables the damage to spread across the joint. To achieve these aims, we have brought together complementary expertise in X-ray nanomechanics (Gupta), cartilage mechanics (Knight), proteomics of ageing tissues (Swift) and synchrotron technology (Terrill), all of whom are internationally leading in their fields.

我们体内的结缔组织是由两个细胞以及细胞周围的纤维基质组成的。纤维基质在赋予组织功能所需的机械性能方面起着主要作用。尽管具有非常不同的功能，但不同软组织的纤维基质在分子水平上由相似的构件组成：胶原分子、由蛋白质(蛋白多糖)连接的长糖链和水。特别是，胶原分子形成细长的纤维，这些纤维与蛋白多糖和水的凝胶状物质一起组装成一个网络。为了在相同的构件上实现一系列不同的功能，不同的软组织通常会改变纤维与蛋白多糖凝胶的相对比例，或者它们的取向或相互连接，以形成非常小规模的复杂复合材料，其厚度低于人类头发的厚度。当我们变老时，结缔组织的特性往往会恶化：例如，在骨关节炎中，皮肤变得更僵硬，软骨破坏。这些不利的更改源于构造块的内部属性或其体系结构的更改。由于这些变化发生在非常小的(纳米)尺度上，因此很难同时找出这种变化及其对力学的影响。为了解决这一问题，我们团队开发了一种高分辨率X射线成像技术，其工作原理类似于胶原蛋白的衍射栅：它可以捕捉组织中纳米级胶原原纤维网络的排列规律，当与非常明亮的X射线源(如同步加速器)一起使用时，可以跟踪原纤维如何拉伸、重新定向或以其他方式响应负荷。在这个项目中，我们将应用这种方法来了解软骨中胶原纤维网络的纳米级机制如何在衰老过程中发生变化。关节软骨在关节中起着无摩擦承力面的作用，缓冲着骨与骨之间的载荷传递。如果负荷过重，纤维基质就会分解，导致骨关节炎、关节疼痛和行动不便。我们的目标是了解胶原蛋白的成分变化如何与其纳米级机械结构的变化联系在一起，并最终导致关节崩溃。我们将把X射线技术与组织中蛋白质组成和结构随年龄变化的高级特征结合起来。这种结合是完全新颖的：X射线技术以前从未被应用于软骨，它与蛋白质组学的结合使结构变化和机械功能之间有了明确的联系。在软骨中，胶原纤维网络抵抗蛋白多糖凝胶的膨胀压力。我们首先的目标是了解这种负载平衡在衰老过程中是如何变化的，并通过改变软骨中不同成分的化学结构和相对比例，了解在分子水平上的变化与破坏力学平衡的机制。其次，我们将研究胶原纤维在受到现实生活中观察到的载荷类型时的实时变形，以及老化如何影响这些动力学。这一点特别重要，因为衰老会导致软骨纤维化和破坏，但胶原蛋白纤维无法抵抗负荷的机制尚不清楚。然后我们将重点介绍两种类型的相关生物力学：重复加载或局部创伤性冲击。首先，我们将调查重复负荷的纤维反应是否在衰老过程中发生变化。然后，我们将用微米级的分辨率绘制局部损伤部位周围的胶原纤维是如何变形的，测试衰老过程中的成分变化使损伤能够扩散到整个关节的假设。为了实现这些目标，我们汇集了X射线纳米力学(Gupta)、软骨力学(Knight)、老化组织蛋白质组学(SWIFT)和同步加速器技术(Terrill)的互补专业知识，所有这些都在各自的领域处于国际领先地位。