Study of the role of secreted platelet thiol isomerases in the regulation of platelet function, haemostasis & thrombosis

分泌型血小板硫醇异构酶调节血小板功能、止血作用的研究

• 批准号: MR/J002666/1
• 负责人: Jonathan Gibbins
• 金额: $ 149.82万
• 依托单位: University of Reading
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2012
• 资助国家: 英国
• 起止时间: 2012 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FJ002666%2F1
• 关键词: Study; role; secreted; platelet; thiol

Platelets are tiny blood cells whose role is to trigger the blood to clot when blood vessels become ruptured during injury. While this is clearly essential to prevent excessive and life-threatening bleeding, abnormal stimulation of blood clotting can be catastrophic, particularly if this leads to the clotting of blood within an artery or vein. This is a condition known as thrombosis, and when this happens in arteries that supply the heart muscle with blood it can cause a heart attack. Thrombosis also commonly occurs in the blood vessels that supply the brain with blood, and in this case it causes strokes. Both of these conditions are very common in the UK and are frequently fatal. The cause of thrombosis in these situations is often underlying diseases such as the formation of fatty lesions in the wall of blood vessels that are liable to rupture, but platelets are ultimately responsible for triggering a dangerous clot to form. The use of drugs to dampen down the responses of platelets has been successful in many 'at risk' patients in the prevention of thrombosis, although many patients gain no benefit and may even suffer side effects such as bleeding. In order to develop better drugs that target platelets to prevent thrombosis, scientists need to know more about how platelets recognise injury, and then stimulate the blood to clot. In this research project we will investigate some proteins known as thiol isomerases that we have found to be released by platelets when they encounter tissue injury. We know that once released some of these molecules attach themselves to the platelet surface and somehow enhance the platelet clotting activity. The purpose of this study is to work out which of the proteins that are released are important to control the functions of platelets in their normal responses and to determine the impact of this on thrombosis. To study thrombosis we will use a newly developed type of microscopy that enables us to visualise thrombosis as it forms within the circulation of mice. Through neutralisation of the function of individual proteins, we will be able to assess their contributions to thrombosis. To begin to work out how to convert these new discoveries into new medicines to prevent thrombosis, it will be important that we understand how these new proteins function on the surface of platelets. Using a range of techniques, and unique reagents that we have developed to study the molecules, we will begin to unravel the biochemical processes that they control and the molecules on the platelet surface that they target. It is anticipated that this project will equip us with a new understanding of how platelets regulate their functions and the identification of the molecules involved. This knowledge may lead, in future studies, to the development of more effective drugs to successfully prevent thrombosis.

血小板是一种微小的血细胞，其作用是在受伤时血管破裂时触发血液凝结。虽然这对于防止过度和危及生命的出血显然是必不可少的，但血液凝固的异常刺激可能是灾难性的，特别是如果这导致动脉或静脉内的血液凝固。这是一种被称为血栓形成的疾病，当这种情况发生在为心肌供血的动脉中时，可能会导致心脏病发作。血栓形成也通常发生在为大脑供血的血管中，在这种情况下，它会导致中风。这两种情况在英国都很常见，而且往往是致命的。在这些情况下，血栓形成的原因通常是潜在的疾病，例如容易破裂的血管壁中脂肪病变的形成，但血小板最终负责触发危险的凝块形成。使用药物抑制血小板的反应在许多“高危”患者中成功地预防了血栓形成，尽管许多患者没有获益，甚至可能出现出血等副作用。为了开发更好的靶向血小板的药物来预防血栓形成，科学家们需要更多地了解血小板如何识别损伤，然后刺激血液凝结。在这个研究项目中，我们将研究一些被称为巯基异构酶的蛋白质，我们发现当血小板遇到组织损伤时，它们会被释放出来。我们知道，一旦释放，这些分子中的一些分子就会附着在血小板表面，并以某种方式增强血小板凝血活性。这项研究的目的是找出释放的蛋白质中哪些对于控制血小板在其正常反应中的功能是重要的，并确定其对血栓形成的影响。为了研究血栓形成，我们将使用一种新开发的显微镜，使我们能够可视化血栓形成，因为它在小鼠的循环中形成。通过中和单个蛋白质的功能，我们将能够评估它们对血栓形成的贡献。为了开始研究如何将这些新发现转化为预防血栓形成的新药，我们必须了解这些新蛋白质在血小板表面的功能。使用一系列的技术，和我们已经开发的独特的试剂来研究这些分子，我们将开始解开它们控制的生化过程和它们靶向的血小板表面上的分子。预计该项目将使我们对血小板如何调节其功能以及相关分子的鉴定有新的认识。在未来的研究中，这些知识可能会导致开发更有效的药物来成功预防血栓形成。

项目成果

Protein Disulphide Isomerase and NADPH Oxidase 1 Cooperate to Control Platelet Function and Are Associated with Cardiometabolic Disease Risk Factors.

• DOI: 10.3390/antiox10030497
• 发表时间: 2021-03-23
• 期刊: Antioxidants (Basel, Switzerland)
• 作者: Gaspar RS;Sage T;Little G;Kriek N;Pula G;Gibbins JM
• 通讯作者: Gibbins JM

A humanized monoclonal antibody that inhibits platelet-surface ERp72 reveals a role for ERp72 in thrombosis.

• DOI: 10.1111/jth.13878
• 发表时间: 2018-03
• 期刊: Journal of thrombosis and haemostasis : JTH
• 作者: Holbrook LM;Sandhar GK;Sasikumar P;Schenk MP;Stainer AR;Sahli KA;Flora GD;Bicknell AB;Gibbins JM
• 通讯作者: Gibbins JM

Intracellular Trafficking, Localization, and Mobilization of Platelet-Borne Thiol Isomerases.

• DOI: 10.1161/atvbaha.116.307461
• 发表时间: 2016-06
• 期刊: Arteriosclerosis, thrombosis, and vascular biology
• 作者: Crescente M;Pluthero FG;Li L;Lo RW;Walsh TG;Schenk MP;Holbrook LM;Louriero S;Ali MS;Vaiyapuri S;Falet H;Jones IM;Poole AW;Kahr WH;Gibbins JM
• 通讯作者: Gibbins JM

Maternal and offspring high-fat diet leads to platelet hyperactivation in male mice offspring.

• DOI: 10.1038/s41598-020-80373-3
• 发表时间: 2021-01-14
• 期刊: Scientific reports
• 影响因子: 4.6
• 作者: Gaspar RS;Unsworth AJ;Al-Dibouni A;Bye AP;Sage T;Stewart M;Wells S;Cox RD;Gibbins JM;Sellayah D;E Hughes C
• 通讯作者: E Hughes C