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

血小板是一种微小的血细胞，它的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出血和危及生命的出血显然是必不可少的，但异常刺激血液凝固可能是灾难性的，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情况，当这种情况发生在为心肌供血的动脉中时，就会导致心脏病发作。血栓形成也经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，如血管壁中容易破裂的脂肪病变的形成，但血小板最终是触发危险凝块形成的原因。在预防血栓形成方面，使用药物抑制血小板反应已在许多“高危”患者中取得成功，尽管许多患者没有获益，甚至可能出现出血等副作用。为了开发针对血小板的更好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硫醇异构酶的蛋白质，我们发现当血小板遇到组织损伤时，它们会释放这些蛋白质。我们知道，一旦这些分子被释放，它们就会附着在血小板表面，以某种方式增强血小板的凝血活性。这项研究的目的是找出释放的哪些蛋白质对控制血小板正常反应的功能很重要，并确定这对血栓形成的影响。为了研究血栓形成，我们将使用一种新开发的显微镜，使我们能够看到血栓形成，因为它在老鼠的循环中形成。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，了解这些新蛋白质如何在血小板表面起作用是很重要的。利用我们开发的一系列技术和独特的试剂来研究这些分子，我们将开始揭示它们控制的生化过程以及它们靶向的血小板表面的分子。预计该项目将使我们对血小板如何调节其功能和识别所涉及的分子有新的认识。在未来的研究中，这一知识可能会导致开发更有效的药物来成功预防血栓形成。

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.