Tissue dependent structure of fibrillin microfibrils

原纤维蛋白微原纤维的组织依赖性结构

• 批准号: BB/N015398/1
• 负责人: Clair Baldock
• 金额: $ 60.04万
• 依托单位: University of Manchester
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2016
• 资助国家: 英国
• 起止时间: 2016 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FN015398%2F1
• 关键词: Tissue; dependent; structure; fibrillin; microfibrils

Fibrillin forms fibres that are important for providing our connective tissues with elasticity such as large blood vessels like the aorta, lungs and skin. Symptoms of ageing associated with a loss of elasticity, for example skin wrinkles, hypertension and eye deterioration, have been linked to degradation of fibrillin. Fibrillin binds to growth factors outside of the cell creating a tissue storage depot. This storage is needed for correct development, repair and maintenance of our tissues, such as the heart, lungs and skin. Binding to fibrillin allows cell signalling to occur correctly to maintain normal tissue structure and function, and are essential in human embryo developmental. Our limited knowledge regarding the structure of fibrillin fibrils presents a major obstacle to understanding their function. The main aim of our work therefore is to understand the structure of the fibrillin fibrils which we believe will allow us to locate the growth factor binding regions, as well as sites important for elastic fibre formation and where cells bind to fibrillin. We will determine what differences occur between fibrillin fibrils from different elastic tissues such as blood vessels and eyes. Finally, we will discover what differences occur in fibrillin fibrils produced at different stages of development, i.e. at birth and in adulthood. Together this will lead to an understanding of how fibrillin fibrils change with tissue type and age and how their structure underpins their important roles in tissue assembly, elasticity and maintenance.Understanding the structure and composition of fibrillin, whose function is to maintain tissue elasticity could have significant health and economic benefits to the UK. Stiffening of the blood vessels and valves of the heart are major causes of heart disease which affects more than 6 million citizens in Europe each year. Heart disease has a huge economic impact, due to the high medical costs and work disability. In the eye, losing elasticity effects the ability to bend the lens (accommodation) which leads to the loss of up-close vision with age. This can be improved by wearing glasses but does not correct completely for this age-related deterioration in vision. Our research findings could be of future interest to the pharmaceutical industry in developing treatments to maintain the elasticity of these tissues and in engineering of replacement biomaterials. Effective treatment would significantly improve the quality of life of an ageing population.

纤维蛋白形成的纤维对于为我们的结缔组织提供弹性是很重要的，例如大血管，如主动脉、肺和皮肤。与弹性丧失相关的衰老症状，例如皮肤皱纹、高血压和眼睛退化，都与纤维蛋白的降解有关。纤维蛋白与细胞外的生长因子结合，形成组织储存库。这种储存是我们的组织，如心脏、肺和皮肤的正确发育、修复和维护所必需的。与纤维蛋白的结合使细胞信号能够正确地发生，以维持正常的组织结构和功能，并且在人类胚胎发育中是必不可少的。我们对纤维蛋白原纤维结构的有限了解是理解其功能的主要障碍。因此，我们工作的主要目的是了解纤维蛋白原纤维的结构，我们相信这将使我们能够定位生长因子结合区，以及对弹性纤维形成和细胞与纤维蛋白结合的重要位置。我们将确定来自不同弹性组织(如血管和眼睛)的原纤维蛋白之间的差异。最后，我们将发现在不同的发育阶段，即出生和成年期，产生的纤维蛋白原纤维有什么不同。总而言之，这将有助于理解纤维蛋白原纤维如何随组织类型和年龄变化，以及它们的结构如何支撑它们在组织组装、弹性和维护中的重要作用。了解纤维蛋白的结构和组成，其功能是维持组织弹性，可能会对英国的健康和经济产生重大好处。心脏血管和瓣膜僵硬是心脏病的主要原因，欧洲每年有600多万人受到心脏病的影响。心脏病有巨大的经济影响，因为高昂的医疗费用和工作残疾。在眼睛中，失去弹性会影响晶状体的弯曲能力(调节)，这会导致随着年龄的增长失去近距离视力。这可以通过戴眼镜来改善，但并不能完全纠正这种与年龄相关的视力下降。我们的研究结果可能对制药行业未来开发保持这些组织弹性的治疗方法和替代生物材料工程感兴趣。有效的治疗将显著提高老龄化人口的生活质量。

项目成果

Structural and compositional diversity of fibrillin microfibrils in human tissues.

• DOI: 10.1074/jbc.ra117.001483
• 发表时间: 2018-04-06
• 期刊: The Journal of biological chemistry
• 作者: Eckersley A;Mellody KT;Pilkington S;Griffiths CEM;Watson REB;O'Cualain R;Baldock C;Knight D;Sherratt MJ
• 通讯作者: Sherratt MJ

Multiscale Imaging Reveals the Hierarchical Organization of Fibrillin Microfibrils.

多尺度成像揭示了纤维蛋白微纤维的分层组织。

• DOI: 10.1016/j.jmb.2018.08.012
• 发表时间: 2018-10-19
• 期刊: Journal of molecular biology
• 影响因子: 5.6
• 作者: Godwin ARF;Starborg T;Smith DJ;Sherratt MJ;Roseman AM;Baldock C
• 通讯作者: Baldock C

Internal cleavage and synergy with twisted gastrulation enhance BMP inhibition by BMPER.

• DOI: 10.1016/j.matbio.2018.08.006
• 发表时间: 2019-04
• 期刊: Matrix biology : journal of the International Society for Matrix Biology
• 作者: Lockhart-Cairns MP;Lim KTW;Zuk A;Godwin ARF;Cain SA;Sengle G;Baldock C
• 通讯作者: Baldock C

Tropoelastin Implants That Accelerate Wound Repair

• DOI: 10.1002/adhm.201701206
• 发表时间: 2018-05-23
• 期刊: ADVANCED HEALTHCARE MATERIALS
• 影响因子: 10
• 作者: Mithieux, Suzanne M.;Aghaei-Ghareh-Bolagh, Behnaz;Weiss, Anthony S.
• 通讯作者: Weiss, Anthony S.

Unraveling the Mechanism of Procollagen C-Proteinase Enhancer

揭示原胶原 C-蛋白酶增强剂的机制

• DOI: 10.1016/j.str.2018.09.003
• 发表时间: 2018
• 期刊: Structure
• 影响因子: 5.7
• 作者: Lockhart-Cairns M