Pericellular mechanisms of fibrillin microfibril assembly.

原纤维蛋白微纤维组装的细胞周机制。

• 批准号: MR/L016540/1
• 负责人: Clair Baldock
• 金额: $ 87.91万
• 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: 2014
• 资助国家: 英国
• 起止时间: 2014 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FL016540%2F1
• 关键词: Pericellular; mechanisms; fibrillin; microfibril; assembly.

Fibrillin microfibrils are filamentous structures laid down by cells as part of the 'extracellular matrix (ECM)'. They form bundles of microfibrils that interact with cells and also form the framework for the formation of 'elastic fibres', which endow the essential property of elastic recoil on dynamic tissues such as blood vessels, lungs, skin and ligaments. The importance of fibrillin is clearly highlighted by the many serious diseases that are caused by genetic defects in fibrillin (e.g. Marfan syndrome, which is associated with life-threatening cardiovascular defects), and by the degeneration of microfibrils in ageing and diseases of blood vessels, lungs (emphysema), loss of skin elasticity, and certain eye defects. Despite their essential nature, it is still not understood how microfibrils form, which has severely limited treatment advances. This proposal is to build on exciting new discoveries from my group which give important new insights into their assembly and function. The study will provide new insights into how mutations in fibrillin-1 cause severe heritable diseases, and form the basis for improved strategies to restore microfibrils to tissues with compromised elasticity. The project is of great importance to regenerative medicine, which is an MRC priority because there is a major unmet clinical need to develop new treatments to restore function to compromised elastic tissues and organs. My group is ideally placed to conduct this specialised research because we are internationally-renowned for our expertise and discoveries in fibrillin/elastic fibre biology, and we will build on our have recent discovery of cell type-specific mechanisms that throw new light on this complex process. Thus it is very timely and directly addresses the MRC Priority 'Resilience, Repair and Replacement'.

原纤维蛋白微纤维是由细胞作为“细胞外基质（ECM）”的一部分铺设的丝状结构。它们形成与细胞相互作用的微纤维束，并且还形成用于形成“弹性纤维”的框架，其赋予动态组织（如血管、肺、皮肤和韧带）弹性反冲的基本性质。许多严重的疾病都是由Ekrain的遗传缺陷引起的（例如马凡氏综合征，它与危及生命的心血管缺陷有关），以及衰老中微纤维的变性和血管疾病，肺（肺气肿），皮肤弹性丧失和某些眼睛缺陷。尽管它们的本质，它仍然不明白微纤维是如何形成的，这严重限制了治疗的进展。这个提议是建立在我的团队令人兴奋的新发现的基础上的，这些发现为它们的组装和功能提供了重要的新见解。这项研究将为研究hepatocin-1突变如何导致严重的遗传性疾病提供新的见解，并为改善弹性受损组织的微纤维恢复策略奠定基础。该项目对再生医学非常重要，这是MRC的优先事项，因为开发新的治疗方法以恢复受损弹性组织和器官的功能是一个重大的未满足的临床需求。我的团队是进行这项专业研究的理想选择，因为我们以其在纤维蛋白/弹性纤维生物学方面的专业知识和发现而享誉国际，我们将在最近发现的细胞类型特异性机制的基础上进一步发展，这些机制为这一复杂过程提供了新的视角。因此，这是非常及时的，直接解决了MRC优先事项“弹性，维修和更换”。

项目成果

Fibrillin microfibrils and elastic fibre proteins: Functional interactions and extracellular regulation of growth factors.

• DOI: 10.1016/j.semcdb.2018.07.016
• 发表时间: 2019-05
• 期刊: Seminars in cell & developmental biology
• 影响因子: 7.3
• 作者: Thomson J;Singh M;Eckersley A;Cain SA;Sherratt MJ;Baldock C
• 通讯作者: Baldock C

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

ADAMTS10-mediated tissue disruption in Weill-Marchesani syndrome.

• DOI: 10.1093/hmg/ddy276
• 发表时间: 2018-11-01
• 期刊: Human molecular genetics
• 影响因子: 3.5
• 作者: Mularczyk EJ;Singh M;Godwin ARF;Galli F;Humphreys N;Adamson AD;Mironov A;Cain SA;Sengle G;Boot-Handford RP;Cossu G;Kielty CM;Baldock C
• 通讯作者: Baldock C

Purification of Recombinant ADAMTSL2.

重组 ADAMTSL2 的纯化。

• DOI: 10.1007/978-1-4939-9698-8_13
• 发表时间: 2020
• 期刊: Methods in molecular biology (Clifton, N.J.)
• 作者: Singh M

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.