Understanding the role of platelets in stroke through comprehensive immunological assessment in relevant clinical cohorts and preclinical models

通过相关临床队列和临床前模型的综合免疫学评估了解血小板在中风中的作用

• 批准号: 2281993
• 金额: --
• 依托单位: University of Manchester
• 依托单位国家: 英国
• 项目类别: Studentship
• 财政年份: 2019
• 资助国家: 英国
• 起止时间: 2019 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=studentship-2281993
• 关键词: Understanding; role; platelets; stroke; through

Stroke affects approximately 100, 000 people each year in the UK, and remains the leading cause of adult disability. The majority of strokes are associated with arterial occlusion (ischaemic stroke: 85%), whilst the remainder are due to haemorrhage into the brain or subarachnoid spaces (haemorrhagic stroke: 15%). Unfortunately, treatment options for ischaemic or haemorrhagic stroke are limited posing a major unmet need for research and clinical practice.It is widely recognised that dysregulated inflammation and thrombosis are strongly implicated in the pathophysiology of stroke disease, both in terms of risk of stroke, and evolution of injury and repair of tissue injury. Further, transient suppression of innate cellular immune responses increases susceptibility to infections after stroke, which occur commonly and adversely impact upon outcomes. Thrombo-inflammatory-immune pathways therefore play a critical part in determining outcomes from stroke and provide opportunities for therapeutic intervention. Platelets are myeloid-derived blood cells which circulate in the blood with a lifespan of 7-10 days. Although they lack a nucleus, they are increasingly recognised as complex cells and contain 3 discreet types of granules (a-granules, dense granules and lysosomes) and residual RNA. Whilst the role of platelets as the primary mediators of thrombosis-haemostasis is long established, they are also increasingly emerging as key mediators of innate immune responses. Platelets directly interact with leucocytes (e.g. monocytes, neutrophils and dendritic cells) via specific surface receptors, forming platelet-leucocyte complexes which influence both innate and adaptive immune responses. Further, platelets can also bind bacteria commonly implicated in stroke-associated infections, and release antimicrobial products which may supplement other innate cellular defence mechanisms. Despite the increasing recognition of platelets in immune responses, the precise functional and clinical relevance of platelet-immune cellular interactions in stroke are poorly characterised or understood. We have recently established comprehensive protocols for mapping immunophenotype and functional status of peripheral blood innate (monocyte, neutrophil) and adaptive (lymphocyte) cellular components and applied these successfully to blood samples from rodents with experimental stroke and patients with stroke. The overall aim of this project is to develop complementary methodologies to evaluate platelets in cerebrovascular disease. The objectives are to establish reproducible protocols for isolating platelets from whole blood samples and for evaluating immunophenotype, leucocyte-binding and functional status. These methods will be applied to blood samples from rodent models of experimental stroke, healthy human controls and patients with acute ischaemic and haemorrhagic stroke.

在英国，中风每年影响大约10万人，并且仍然是成人残疾的主要原因。大多数中风与动脉闭塞有关（缺血性中风：85%），而其余的是由于脑或蛛网膜下腔出血（出血性中风：15%）。不幸的是，缺血性或出血性卒中的治疗选择是有限的，这对研究和临床实践提出了主要的未满足的需求。人们普遍认为，失调的炎症和血栓形成强烈地涉及卒中疾病的病理生理学，无论是在卒中的风险方面，还是在损伤的演变和组织损伤的修复方面。此外，先天性细胞免疫应答的短暂抑制增加了中风后感染的易感性，这通常发生并对结果产生不利影响。因此，血栓-炎症-免疫途径在决定卒中结局方面发挥着关键作用，并为治疗干预提供了机会。血小板是骨髓来源的血细胞，在血液中循环，寿命为7-10天。虽然它们缺乏细胞核，但它们越来越被认为是复杂的细胞，含有3种离散类型的颗粒（α-颗粒，致密颗粒和溶酶体）和残留的RNA。虽然血小板作为血栓形成-止血的主要介质的作用早已确立，但它们也越来越多地成为先天免疫应答的关键介质。血小板通过特异性表面受体直接与白细胞（如单核细胞、中性粒细胞和树突细胞）相互作用，形成血小板-白细胞复合物，影响先天性和适应性免疫应答。此外，血小板还可以结合通常与中风相关感染有关的细菌，并释放可补充其他先天细胞防御机制的抗菌产物。尽管血小板在免疫应答中的作用越来越受到重视，但血小板-免疫细胞相互作用在卒中中的确切功能和临床相关性的特征或理解却很差。我们最近建立了全面的协议映射免疫表型和外周血先天性（单核细胞，中性粒细胞）和适应性（淋巴细胞）细胞成分的功能状态，并成功地应用这些血液样本从啮齿动物与实验性中风和中风患者。该项目的总体目标是开发辅助方法来评估脑血管疾病中的血小板。目的是建立从全血样品中分离血小板和评价免疫表型，白细胞结合和功能状态的可重复的协议。这些方法将应用于实验性中风的啮齿动物模型、健康人对照和急性缺血性和出血性中风患者的血液样本。