Thiol Isomerases in Hemostasis and Thrombosis

项目摘要 血管硫醇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裂解多肽键。硫醇异构酶和丝氨酸 蛋白水解酶在血管损伤部位积累，两者都是血栓形成所必需的。 队形。然而，尽管我们对丝氨酸蛋白酶如何促进凝血的了解很深， 关于硫醇异构酶在血栓形成中的作用，人们知之甚少。虽然我们已经使用了我们的 凝血因子用于血栓性疾病治疗的知识，缺点 目前抗血栓药物的有效性和安全性都表明有必要利用新的知识 血栓形成的替代介质，如硫醇异构酶，以利于治疗。 我们已经确定了新的蛋白质二硫键异构酶(PDI)抑制剂，并证明了 它们在临床前模型中的有效性。我们目前正在进行第二阶段/第三阶段的临床试验测试 我们的PDI抑制剂之一在癌症治疗中的抗血栓潜力。我的研究 计划将重点放在硫醇异构酶在止血和血栓形成中的作用 确定硫醇异构酶促进血栓形成的机制的目的 硫醇异构酶靶向治疗的疾病过程的形成和识别 被用于治疗。我们的研究将改变硫醇异构酶在止血方面的领域 和血栓形成通过以下进展：(A)全面了解血管 硫醇异构酶参与血栓形成，包括血管硫醇异构酶是如何 它们作为氧化还原感受器的机制，以及它们的鉴定 血栓形成的底物，(B)硫醇异构酶影响血栓形成的确凿证据 止血和血栓形成不同，(C)凝血疾病和血栓形成的鉴定 可使用硫醇异构酶靶向治疗或诊断的疾病，以及(D) 介绍硫醇异构酶靶向试剂的临床应用。在未来的7年里，我们 将评估硫醇异构酶在脓毒症相关血栓形成中的作用，可遗传 高凝状态、抗磷脂综合症和癌症。因此，该计划将 阐述硫醇异构酶如何启动血栓形成和 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.