分泌型二硫键异构酶ERp46对血小板整合素αIIbβ3的氧化还原调控

阐明整合素αIIbβ3的调节机制是了解血小板生物学和血栓性疾病的关键。二硫键异构酶（PDI）家族共有20个成员，其主要功能是调控蛋白二硫键的氧化还原。我们和其他学者近来报导ERp57、PDI、ERp72、ERp5和TMX1等成员通过氧化还原调控αIIbβ3，参与血小板活化和血栓形成，但其他成员的作用及调控机制不清楚。我们最近发现ERp46血小板特异性敲除小鼠存在出血倾向，且体内血小板积聚和体外血小板活化均受抑制，提示ERp46促进血小板活化和血栓形成。更重要的是，ERp46还原αIIbβ3的作用比PDI、ERp57、ERp5、ERp72等更早、更强。由此我们首次提出ERp46是调控αIIbβ3的“主开关”学说。本项目中我们将应用基因敲除小鼠模型、iodo-TMT标记巯基以及质谱检测等综合手段，深入研究ERp46对整合素αIIbβ3的氧化还原调控机制，力图为血栓性疾病的治疗提供新的干预靶点。

Elucidating the regulation mechanism of integrin αIIbβ3 is key to understand platelet biology and thrombotic diseases pathogenesis. There are 20 members in the protein disulfide isomerase (PDI) family, whose main function is to regulate the oxidation and reduction of disulfide bonds in proteins. We and others recently reported that some PDI family members such as ERp57, PDI, ERp72, ERp5, and TMX1 regulate αIIbβ3 through redox reaction which is involved in platelet function and thrombosis. However, whether other members are involved and what their regulatory role and mechanism are remain unclear. Recently, our preliminary data showed that the deficiency of ERp46 caused the defective hemostasis, reduced platelet accumulation and impaired platelet activation, suggesting that ERp46 positively regulates platelet activation and thrombosis. More importantly, we found that the reduction of αIIbβ3 by ERp46 occurs earlier and stronger than other members such as PDI, ERp57, ERp5, and ERp72. Therefore, we hypothesize that ERp46 is the "Master Switch" that regulates αIIbβ3. To test this hypothesis, we will use comprehensive strategies such as gene knockout mouse models, iodo-TMT labeling approach, mass spectrometry detection and analysis to conduct in-depth mechanistic research. These results will improve our knowledge of the redox regulation mechanism of ERp46 on integrin αIIbβ3, and will reveal new therapeutic target for anti-thrombotic treatment.