Thiol Isomerases in Hemostasis and Thrombosis

项目摘要 血管巯基异构酶在血栓形成过程中以某种方式修饰二硫键 类似于丝氨酸蛋白酶如何切割肽键。巯基异构酶和丝氨酸 蛋白酶在血管损伤部位积聚， 阵然而，虽然我们对丝氨酸蛋白酶如何促进凝血的了解很深， 关于巯基异构酶在血栓形成中的作用知之甚少。虽然我们已经使用了我们的 凝血因子的知识，以开发血栓性疾病的治疗方法， 目前抗血栓药物的有效性和安全性表明需要利用新的知识， 血栓形成的替代介质，如硫醇异构酶，用于治疗益处。 我们已经鉴定了蛋白质二硫键异构酶（PDI）的新型抑制剂，并证明了 其在临床前模型中的功效。我们目前正在进行II/III期临床试验测试 我们的PDI抑制剂在癌症背景下的抗血栓形成潜力。我的研究 该计划将侧重于巯基异构酶在止血和血栓形成中的作用， 目的是确定巯基异构酶促进血栓形成的机制 形成和鉴定疾病过程，其中硫醇异构酶靶向治疗可以 用于治疗。我们的研究将改变巯基异构酶在止血中的应用领域 和血栓形成的以下进展：（一）全面了解如何血管 巯基异构酶参与血栓形成，包括血管巯基异构酶如何 调节，它们作为氧化还原传感器的机制，以及它们的识别 血栓形成中的底物，（B）硫醇异构酶影响 止血和血栓形成不同，（c）凝血病和血栓形成的鉴定 可以使用硫醇异构酶靶向疗法或诊断的疾病，和（d） 巯基异构酶靶向试剂的临床应用。在接下来的7年里，我们 将评估巯基异构酶在与败血症、遗传性 高凝状态、抗磷脂综合征和癌症。因此，该方案将 解决硫醇异构酶如何启动血栓形成的基础生物学， 确定他们参与的血栓性疾病。

Project Summary Vascular thiol isomerases modify disulfide bonds during thrombus formation in a manner analogous to how serine proteases cleave peptide bonds. Both thiol isomerases and serine proteases accumulate at sites of vascular injury and both are absolutely required for thrombus formation. Yet, while our knowledge of how serine proteases contribute to coagulation is deep, little is known about how thiol isomerases function in thrombosis. And while we have used our knowledge of coagulation factors to develop treatments for thrombotic disease, shortcomings of current antithrombotics in both efficacy and safety indicate a need to leverage new knowledge of alternative mediators of thrombus formation, such as thiol isomerases, for therapeutic benefit. We have identified novel inhibitors of protein disulfide isomerase (PDI) and have demonstrated their efficacy in pre-clinical models. We are currently conducting a phase II/III clinical trial testing the antithrombotic potential one of our PDI inhibitors in the setting of cancer. My research program will focus on the role of thiol isomerases in hemostasis and thrombosis with the objectives of determining the mechanisms by which thiol isomerases contribute to thrombus formation and identifying disease processes in which thiol isomerase-targeted therapies could be used therapeutically. Our studies will transform the field of thiol isomerases in hemostasis and thrombosis by the following advances: (a) a comprehensive understanding of how vascular thiol isomerases participate in thrombosis including how vascular thiol isomerases are regulated, the mechanism by which they act as redox sensors, and the identification of their substrates in thrombus formation, (b) conclusive evidence that thiol isomerases affect hemostasis and thrombosis differently, (c) the identification of coagulopathies and thrombotic diseases in which thiol isomerase-targeted therapies or diagnostics can be used, and (d) the introduction of thiol isomerase-targeted reagents in clinical practice. Over the next 7 years, we will evaluate the role of thiol isomerases in thrombosis associated with sepsis, inheritable hypercoagulable states, anti-phospholipid syndrome, and cancer. This program will thus address the fundamental biology of how thiol isomerases initiate thrombus formation and identify thrombotic diseases in which they participate.