Integrating modelling and experimental approaches to investigate adventitious age-related collagen crosslinking in skeletal tissues

整合模型和实验方法来研究骨骼组织中与年龄相关的外来胶原蛋白交联

• 批准号: BB/K007785/1
• 负责人: Helen Birch
• 金额: $ 88.03万
• 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: 2013
• 资助国家: 英国
• 起止时间: 2013 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FK007785%2F1
• 关键词: Integrating; modelling; experimental; approaches; investigate

As we age our tendons, ligaments and bones begin to function less well, resulting in stiffness, reduced mobility and increased frailty. In some individuals this occurs to such an extent that they suffer considerable pain and are unable to undertake daily activities, let alone exercise to maintain good health. Tendons - the soft connective tissues that connect muscles to bone - are particularly vulnerable to age related changes. It is well known that proteins, such as collagen that forms the main force-resisting component of tendon, are susceptible to modification by sugars in the blood. The addition of sugars to collagen results in cross-links forming between neighbouring collagen molecules. Tendon, ligament and bone are composed of the same type of collagen and therefore it is likely that the same sugar mediated crosslinks will form. Although these cross-links are recognised to have a detrimental effect on collagen properties, they have been notoriously difficult to study. Recent advances in mass spectrometry of proteins, computer modelling studies and nano-scale mechanics have made it possible to study these age-related modifications to proteins in much more detail. In our study we will quantify and locate levels of important sugar-mediated cross-links in tendons from individuals of different ages and link this to how the collagen structures perform mechanically and renew themselves within the tendon tissue. In addition, we will investigate ligament and bone tissue to determine whether a similar pattern and level of age related crosslinking is present suggesting commonality in ageing of different skeletal tissues. Glycation mediated cross-links are likely modified by diet, exercise and pharmacological agents and this may provide an opportune way of intervening to reduce the impact of normal ageing and risk of frailty and poor health. The findings of this study have great potential to improve the quality of life and wellbeing into old age in a large proportion of the population.

随着年龄的增长，我们的肌腱、韧带和骨骼开始功能下降，导致僵硬、活动能力降低和脆弱性增加。在一些人中，这种情况发生到这样的程度，他们遭受相当大的痛苦，无法进行日常活动，更不用说锻炼以保持良好的健康。肌腱-连接肌肉和骨骼的软结缔组织-特别容易受到年龄相关变化的影响。众所周知，蛋白质，如胶原蛋白，形成肌腱的主要阻力成分，容易受到血液中糖的修饰。向胶原蛋白中添加糖导致相邻胶原蛋白分子之间形成交联。肌腱、韧带和骨由相同类型的胶原蛋白组成，因此可能会形成相同的糖介导的交联。虽然这些交联被认为对胶原蛋白的性质有不利影响，但它们一直难以研究。最近在蛋白质质谱、计算机建模研究和纳米尺度力学方面的进展，使我们有可能更详细地研究这些与年龄有关的蛋白质修饰。在我们的研究中，我们将量化和定位不同年龄个体肌腱中重要的糖介导的交联水平，并将其与胶原结构如何在肌腱组织内机械地进行和自我更新联系起来。此外，我们将研究韧带和骨组织，以确定是否存在类似的模式和水平的年龄相关交联，这表明不同骨骼组织老化的共性。糖基化介导的交联可能通过饮食、运动和药物进行修饰，这可能提供一种适当的干预方式，以减少正常衰老的影响以及虚弱和健康状况不佳的风险。这项研究的结果具有很大的潜力，可以改善大部分人口的生活质量和老年健康。

项目成果

Preferential sites for intramolecular glucosepane cross-link formation in type I collagen: A thermodynamic study.

• DOI: 10.1016/j.matbio.2015.06.001
• 发表时间: 2015-10
• 期刊: Matrix biology : journal of the International Society for Matrix Biology
• 作者: Collier TA;Nash A;Birch HL;de Leeuw NH
• 通讯作者: de Leeuw NH

Effect on the mechanical properties of type I collagen of intra-molecular lysine-arginine derived advanced glycation end-product cross-linking.

对分子内赖氨酸 - 精氨酸衍生的晚期糖基化最终产物交联的I型胶原蛋白的机械性能的影响。

• DOI: 10.1016/j.jbiomech.2017.11.021
• 发表时间: 2018-01-23
• 期刊: Journal of biomechanics
• 影响因子: 2.4
• 作者: Collier TA;Nash A;Birch HL;de Leeuw NH
• 通讯作者: de Leeuw NH

The thermodynamic identification of glucosepane cross-linking in type I collagen - an all atom molecular dynamics study

I型胶原蛋白中葡萄糖烷交联的热力学鉴定——全原子分子动力学研究

• 发表时间: 2015
• 期刊: INTERNATIONAL JOURNAL OF EXPERIMENTAL PATHOLOGY
• 影响因子: 3
• 作者: Collier T.

Glucosepane: investigating formation and structure in tendon collagen

Glucosepane：研究肌腱胶原蛋白的形成和结构

• 发表时间: 2015
• 期刊: INTERNATIONAL JOURNAL OF EXPERIMENTAL PATHOLOGY
• 影响因子: 3
• 作者: Lopez-Clavijo A. F.

Combining nano-physical and computational investigations to understand the nature of "aging" in dermal collagen.

• DOI: 10.2147/ijn.s121400
• 发表时间: 2017
• 期刊: International journal of nanomedicine
• 影响因子: 8
• 作者: Ahmed T;Nash A;Clark KE;Ghibaudo M;de Leeuw NH;Potter A;Stratton R;Birch HL;Enea Casse R;Bozec L
• 通讯作者: Bozec L