Development of a fully humanised model for understanding platelet function

血小板是血液中的小细胞，当它被激活时，在防止损伤部位过度出血方面起着关键作用。相反，不适当的血小板激活会阻断心脏和大脑的血液供应，导致危及生命的心脏病发作或中风，并导致约40%的心血管死亡。目前预防心脏病发作和中风的治疗是基于抑制正常血小板功能的药物。虽然对大约三分之二的患者有效，但其余的患者会再次心脏病发作或中风。由于抗血小板药物会抑制正常的血小板功能，它们也会产生令人讨厌的出血的副作用，在某些情况下，出血会成为患者的严重并发症。因此，了解控制血小板活化和功能的分子机制，以及血小板如何与受损血管壁相互作用，对于了解血小板如何影响健康和疾病，以及确定新的和改进的药物靶点是必要的。直接在人身上研究这些事件是不道德的，而血小板研究目前严重依赖于使用转基因小鼠模型来了解蛋白质或特定蛋白质结构域如何在血小板功能中发挥作用。然而，小鼠模型并不总是研究人类血小板功能的合适选择，需要人类血管模型。这个项目将第一次汇集一个模型，用一种允许修改人类血小板的方法来复制人类血管。这将使新的药物靶点能够使用人体组织进行研究和测试，减少并取代心血管研究中动物的使用。

Platelets are small cells in the blood which, when activated, play a critical role in the prevention of excessive bleeding at sites of injury. Conversely, inappropriate platelet activation can block the blood supply to the heart and brain resulting in life threatening heart attacks or strokes and contribute to an estimated 40% of cardiovascular deaths. Current therapy in the prevention of heart attacks and strokes is based on drugs which suppress normal platelet function. While effective in approximately two thirds of patients, the remainder succumb to a second heart attack or stroke. As anti-platelet drugs suppress normal platelet function they can also have the undesirable side effect of nuisance bleeding, which can in some cases become a serious complication for patients. Therefore, an understanding of the molecular mechanisms governing platelet activation and function and how platelets interact with a damaged blood vessel wall is needed to understand how platelets impact health and disease and for the identification of new and improved drug targets. It is not ethical to study these events directly in people and platelet research is currently heavily reliant on the use of genetically altered mouse models to understand how proteins or specific protein domains play a role in platelet function. However, mouse models are not always a suitable alternative to investigate human platelet function and a model of the human blood vessel is needed. This project will, for the first time, bring together a model to replicate the human blood vessel with a method that will allow human platelets to be modified. This will enable new drug targets to be studied and tested using human tissue, reducing and replacing the use of animals in cardiovascular research.