Gi-Proteins and platelets

血小板活化不仅是正常止血所必需的，而且也是中风或心肌梗死等急性缺血性疾病状态下的主要病理机制。因此，包括Gi蛋白偶联受体在内的多种细胞表面受体严密控制着血小板的功能。例如，Gi蛋白偶联的P2Y12受体传递激动剂诱导的血小板激活，导致血小板聚集。P2Y12受体是拮抗剂的治疗靶点，它增加了出血的风险。在已知的三种受体偶联的Galpha-I亚型中，我们证实了Galpha-I2和Galpha-I3在小鼠血小板中的表达。在我们之前的工作中，我们证明了Galpha-I亚型与血小板功能的不同相关。然而，其潜在的机制仍有待阐明。我们假设Galpha-I2和Galpha-I3在血小板中既有重叠的功能，也有独立的功能，并且这两种亚型对止血、血栓形成和炎症的调节不同。在拟议的项目中，我们想要(1)研究哪些功能是由Galpha-i2和Galpha-i3选择性或冗余地调节的，(2)识别涉及Galpha-I信号的调节器和效应器，以及(3)破译Galpha-I控制的止血和炎症反应的分子机制。

Platelet activation is not only essential for normal haemostasis but also a major pathomechanism underlying acute ischemic disease states such as stroke or myocardial infarction. Hence, platelet function is under tight control by various cell surface receptors including Gi-protein-coupled receptors. For instance Gi-protein-coupled P2Y12-receptors transmit agonist-induced platelet activation leading to platelet aggregation. P2Y12-receptors are therapeutically targeted by antagonists, which harbor an increased risk for bleeding. Of the three known receptor-coupled Galpha-i-isoforms, we confirmed expression of Galpha-i2 and Galpha-i3 in murine platelets. In our previous work, we demonstrated that Galpha-i-isoforms are differentially involved in platelet functions. However, the underlying mechanisms remain to be elucidated. We hypothesize that Galpha-i2 and Galpha-i3 have both overlapping as well as independent functions in platelets and that both isoforms differently regulate haemostasis, thrombus formation and inflammation. In the proposed project, we want to (1) examine which functions are selectively or redundantly regulated by Galpha-i2 and Galpha-i3 in platelets, (2) identify the regulators and effectors involved in Galpha-i-signaling, and (3) decipher the molecular mechanisms underlying Galpha-i-governed haemostasis and inflammatory responses.