血小板Rubicon分子影响缺血性脑卒中的关键作用和机制研究

血小板活化导致的病理性血栓是心肌梗塞、脑卒中等致死致残性重大疾病的直接原因,但生理性止血也依赖于血小板活化，寻找区分病理性血栓和生理性止血的血小板调控靶点是本领域重大科学问题。实验室前期发现并报道了抑制血栓但不影响止血的血小板活化调控新分子VPS34。本项目中，前期的预实验发现血小板高表达VPS34调控网络中的重要蛋白Rubicon，初步筛查证实Rubicon对血小板表面受体GPVI介导的活化具有特异性的负向调控作用。而且血小板中的Rubicon在缺血性脑卒中的病理模型中显示具有抑制卒中的关键作用。该结果提示血小板Rubicon是缺血性脑卒中的病理过程中发挥独特作用的全新的重要分子，是该疾病的潜在治疗靶点。本项目拟通过血小板特异性Rubicon基因敲除小鼠和分子生物学研究手段，明确Rubicon调控的血小板信号以及在缺血性脑卒中疾病中的功能机制，为缺血性脑卒中的干预提供新的安全分子靶点。

Platelet activation is responsible for major cardio-cerebrovascular diseases, but it is also key to hemostasis. It is imperative to identify platelet molecules capable of differentiating hemostasis from thrombosis. Fueled by our previous findings that class III PI3K VPS34 is one of such safe targets whose absence inhibits thrombosis while spares hemostasis, we recently identified a novel VPS34-regulating protein, namely, Rubicon (Run domain protein as Beclin-1 interacting and cystein-rich containing). Using megakaryocyte/platelet-specific Rubicon-deficient mice, the preliminary results indicated that Rubicon has a selective inhibiting role for platelet GPVI signaling. Importantly, our data also indicate that Rubicon may be a vital regulator in the pathogenesis of ischemic stroke with translational potentials. By further elucidating the pathophysiological role of Rubicon in thrombotic disease and delineating the platelet signaling network regulated by Rubicon, this project aims to provide novel molecular markers and intervention targets for ischemic stroke.