核受体FXR在无核血小板中的表达和功能

Farnesoid X receptor (FXR) is a nuclear receptor mainly expressed in the liver and gastrointestinal system. In nuclear cells, upon activation by its physiological ligand bile acid, FXR acts as a transcription factor to regulate its target gene transcription. The expression and function of FXR in nuclear cells has been fully investigated. However, its expression and function in anucleate platelets still remains unclear. Here, for the first time,we reported that the FXR is highly expressed in human platelet, We also found that FXR agonist inhibits platelets aggregation and spreading. FXR directly interacts with Gq protein, which plays an important role in platelet activation signal transduction. Based on our previous studies, we hypothesized that FXR is functionally expressed in platelet. We plan to study the effect and underlying mechanism of FXR agonists on platelet adhesion, aggregation, spreading and retraction. Using FXR knockout mice, we plan to investigate the role of FXR and its agonists in platelet activation and thrombosis formation. Finally, we intend to study the correlation between bile acid levels and platelet reactivities in cholestasis patients. Our project will provide important new knowledge in the non-genomic effects of FXR (its effects on platelet activation and thrombus formation). Our project also provides a new potential target of anti-platelet therapy. Considering that there is an ongoing phase III clinical trial to assess the effects of FXR agonist (6E-CDCA) in primary biliary cirrhosis, our plan will expand the new pharmacological effects of FXR agonists.

血小板异常激活引起的血管内血栓形成是动脉血栓性疾病的重要病理基础，现有的抗血小板药在治疗上仍然存在严重副作用，发现抗血小板激活的新靶点及相关分子机制研究十分重要。我们前期工作中发现，无核血小板中核受体FXR高表达, 活化FXR显著抑制人血小板聚集和铺展活化反应，活化的FXR与介导血小板活化的重要信号蛋白Gq蛋白直接相互作用。提示活化的FXR抗血小板激活可能通过与Gq蛋白相互作用，从而抑制Gq介导的血小板活化信号实现。本项目拟使用FXR基因敲除小鼠、血栓动物模型、FXR激活患者血小板等，深入研究FXR对血小板聚集，粘附，铺展，回缩等特征的影响及其分子机制，并评价FXR激动剂在血小板激活、血栓形成中的作用。本项目的完成不仅可能为寻找新的抗血小板药物靶点提供理论依据，而且可能拓展部分已进入III 期临床试验，用于治疗肝脏代谢疾病的FXR受体激动剂的新的药理作用。

血小板异常激活引起的血管内血栓形成是动脉血栓性疾病的重要病理基础，发现抗血小板激活的新靶点及相关分子机制研究十分重要。血小板具有许多转录因子，这些转录因子可通过不依赖DNA的机制调节其功能。包括法尼醇X受体（FXR），它是转录因子超家族的成员，内源性配体为胆汁酸。我们发现，无核血小板中核受体FXR高表达, FXR激动剂抑制胶原或凝血酶诱导的血小板活化，减少血小板的钙动员，削弱纤维蛋白原结合和血小板释放反应。FXR激动剂还减少了整联蛋白αIIbβ3的由内而外的信号传导，从而显著抑制人血小板聚集和铺展活化反应，活化的FXR与介导血小板活化的重要信号蛋白Gq蛋白直接相互作用。从而抑制Gq介导的血小板活化信号。FXR敲除小鼠的血小板对FXR激动剂对血小板功能的作用不敏感，表明这些配体通过FXR受体发挥作用。这项研究为FXR激动剂抑制血小板活化的能力提供了证据，FXR激动剂抗动脉粥样硬化作用及抗血小板作用表明FXR是预防动脉粥样硬化血栓形成疾病的潜在靶标，具有临床应用前景。.。