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Exploring bias in platelet P2Y1 receptor signalling: host defence versus haemostasis.

探索血小板 P2Y1 受体信号传导的偏差：宿主防御与止血。

基本信息

批准号：
MR/T015845/1
负责人：
Simon Pitchford
金额：
$ 101.3万
依托单位：
King's College London
依托单位国家：
英国
项目类别：
Research Grant
财政年份：
2020
资助国家：
英国
起止时间：
2020 至无数据
项目状态：
未结题

来源：
https://gtr.ukri.org/projects?ref=MR%2FT015845%2F1
关键词：
Exploring bias platelet P2Y1 receptor

项目摘要

Blood contains cells to kill germs. In order to defend us against germs, they need to leave the bloodstream and travel through the inflamed tissue to reach the germs, engulf them and secrete materials that help kill them. The body does this via a protective mechanism called the inflammatory response. Sometimes this inflammatory response occurs inappropriately in diseases unrelated to infection, which then unfortunately causes self-inflicted harm to the body, for example in asthma, chronic obstructive pulmonary disease (COPD, mostly caused by smoking), or inflammation caused by sudden trauma. Previously, our research group have discovered that white blood cells called leukocytes require the help of yet another blood cell type, the platelets, to be able to migrate from the blood stream to sites of inflammation and infection. Platelets are best known for forming blood clots, thereby preventing us from bleeding to death every time we have an injury (this process is known as haemostasis), but because they also guide the white blood cells to reach inflamed organs as well as helping the white blood cells to fight and kill germs, they are also indispensable for our immune system. Yet, the processes of haemostasis and inflammation are distinct. The main aim of our research project here is to learn how platelets get activated in response to the protective process of inflammation, without affecting the essential process of haemostasis, because this might lead to excessive bleeding, or blood clots. Research into how platelets become activated during inflammation is important for basic science, but also because current medical treatments are just not good enough. We require better medicines - because 5.4 million people in the United Kingdom suffer from asthma, and 1.2 million suffer from COPD. Despite better management of patients, and the introduction of new drugs, 3 people die every day in the UK as a result of an asthma attack, 80 people die every day as a result of COPD, and people who have inflammation of the lungs associated with acute trauma or pneumonia have between a 20 and 50% death rate. If we can find new ways of modulate platelet activity at the site of inflammation, without affecting normal blood clotting, we might be able to create new medicines that improve the health of millions of people.Platelets express proteins called purinergic receptors that are important for switching platelets 'on' during blood clotting, but when certain types of purinergic receptors get switched 'on' in an inflammatory environment, they boost activity to help fight germs instead of forming blood clots. We will research how a particular purinergic receptor (P2Y1) works to control platelet activity during inflammation, compared to their function in blood clotting. To do this, we have assembled a team of scientists from within King's College London, with different areas of expertise (computer modellers, synthetic chemists, pharmacologists) to create new molecules that are designed to change P2Y1 function. Receptors change shape continuously, and depending on what shape they are, when activated, platelets will function differently based on the shape or conformation of the receptor. The new molecules will be designed to bind to P2Y1 when it is a particular shape. We hope to change selective functions of platelets necessary for inflammation, to fight infection, or for clotting of blood. Together, we will create a library of these molecules to be used as research tools (called 'biased' agonists-activation antagonists-blocking) after computer-aided modelling. We will measure the functions of platelets in the presence of these agonists and antagonists, and their effects on white blood cell activation, both in the test tube and in actual inflammation and infection. This research project will help us and other scientists understand exactly how P2Y1 on platelets works during inflammation compared to blood clotting.

血液中含有杀死细菌的细胞。为了保护我们免受细菌的侵害，它们需要离开血液，穿过发炎的组织到达细菌，吞噬它们，并分泌有助于杀死细菌的物质。身体通过一种叫做炎症反应的保护机制来做到这一点。有时，这种炎症反应不适当地发生在与感染无关的疾病中，然后不幸地对身体造成自我伤害，例如哮喘、慢性阻塞性肺疾病（COPD，主要由吸烟引起）或突发创伤引起的炎症。此前，我们的研究小组发现，白细胞需要另一种血细胞——血小板的帮助，才能从血流中迁移到炎症和感染部位。血小板最著名的功能是形成血块，从而防止我们每次受伤时因失血过多而死亡（这个过程被称为止血），但因为它们也引导白细胞到达发炎的器官，并帮助白细胞对抗和杀死细菌，它们对我们的免疫系统也是不可或缺的。然而，止血和炎症的过程是不同的。我们在这里的研究项目的主要目的是了解血小板如何在不影响止血的基本过程的情况下被激活，以应对炎症的保护过程，因为这可能导致过度出血或血栓。研究血小板在炎症期间如何被激活对基础科学很重要，但也因为目前的医学治疗还不够好。我们需要更好的药物——因为英国有540万人患有哮喘，120万人患有慢性阻塞性肺病。尽管对病人进行了更好的管理，并引入了新药，但在英国，每天仍有3人死于哮喘发作，80人死于慢性阻塞性肺病，而与急性创伤或肺炎相关的肺部炎症患者的死亡率在20%至50%之间。如果我们能找到在不影响正常血液凝结的情况下调节炎症部位血小板活动的新方法，我们就有可能创造出改善数百万人健康的新药。血小板表达一种叫做嘌呤能受体的蛋白质，这种蛋白质对血小板在血液凝固过程中“开启”至关重要，但当某些类型的嘌呤能受体在炎症环境中“开启”时，它们会增强活性，帮助对抗细菌，而不是形成血栓。我们将研究一种特定的嘌呤能受体（P2Y1）如何在炎症期间控制血小板活性，与它们在血液凝固中的功能相比。为了做到这一点，我们从伦敦国王学院召集了一个科学家团队，他们拥有不同领域的专业知识（计算机建模师，合成化学家，药理学家）来创造旨在改变P2Y1功能的新分子。受体的形状会不断变化，这取决于它们的形状，当被激活时，血小板会根据受体的形状或构象发挥不同的功能。新分子将被设计成在P2Y1具有特定形状时与之结合。我们希望改变血小板在炎症、抗感染或凝血中所必需的选择性功能。在计算机辅助建模后，我们将共同创建一个这些分子库，用作研究工具（称为“偏倚”激动剂-激活拮抗剂-阻断）。我们将测量血小板在这些激动剂和拮抗剂存在下的功能，以及它们在试管和实际炎症和感染中对白细胞激活的影响。这个研究项目将帮助我们和其他科学家准确地了解血小板上的P2Y1与血液凝固相比在炎症过程中是如何起作用的。

项目成果

期刊论文数量（8）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Current Trends and Future Approaches in Small-Molecule Therapeutics for COVID-19.

DOI：
10.2174/0929867327666200721161840
发表时间：
2021
期刊：
Current medicinal chemistry
影响因子：
4.1
作者：
Laws M;Surani YM;Hasan MM;Chen Y;Jin P;Al-Adhami T;Chowdhury M;Imran A;Psaltis I;Jamshidi S;Nahar KS;Rahman KM
通讯作者：
Rahman KM

Platelet purinergic receptors and non-thrombotic diseases.

血小板嘌呤能受体和非血栓性疾病。