Thiol Isomerases in Hemostasis and Thrombosis

硫醇异构酶在止血和血栓形成中的作用

• 批准号: 10549734
• 负责人: Robert C Flaumenhaft
• 金额: $ 91.76万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-02-01 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10549734
• 关键词: Address; Affect; Antiphospholipid Syndrome; Biology; Blood Circulation; Blood Coagulation Disorders; Blood Coagulation Factor; Blood Vessels; Blood coagulation; Coagulation Process; Diagnostic; Disease; Enzymes; Fibrinolytic Agents; Hemostatic function; Inherited; Isomerase; Knowledge; Malignant Neoplasms; Mediator; Myocardial Infarction; Oxidation-Reduction; Patients; Peptides; Phase II/III Clinical Trial; Pre-Clinical Model; Process; Protein Disulfide Isomerase; Reagent; Research; Role; Safety; Sepsis; Serine Protease; Site; Stroke; Sulfhydryl Compounds; Testing; Therapeutic; Therapeutic Agents; Therapeutic Uses; Thrombophilia; Thrombosis; Thrombus; Venous; clinical practice; disulfide bond; inhibitor; novel; novel diagnostics; novel therapeutics; prevent; programs; sensor; targeted treatment; thrombotic; vascular injury

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.

项目摘要 血管硫醇异构酶以某种方式改变血栓形成期间的二硫键键 类似于丝氨酸蛋白酶如何切割肽键。硫醇异构酶和丝氨酸 蛋白酶在血管损伤部位积聚，两者绝对需要血栓 形成。然而，尽管我们对丝氨酸蛋白酶如何有助于凝血的了解很深，但 关于硫醇异构酶在血栓形成中的功能知之甚少。而我们已经使用了 了解凝血因素以开发血栓性疾病的治疗方法， 当前在疗效和安全性方面的反物质学表明需要利用新知识 血栓形成的替代介质（例如硫醇异构酶）为治疗益处。 我们已经确定了蛋白质二硫化物异构酶（PDI）的新型抑制剂，并证明了 它们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 在癌症的情况下，我们的PDI抑制剂之一。我的研究 程序将重点介绍硫醇异构酶在止血和血栓形成中的作用 确定硫醇异构酶有助于血栓的机制的目标 形成和识别硫醇异构酶靶向疗法的疾病过程 在治疗上使用。我们的研究将改变止血中硫醇异构酶的领域 和血栓形成以下进展：（a）对血管的全面理解 硫醇异构酶参与血栓形成，包括血管硫醇异构酶 受监管，它们充当氧化还原传感器的机制以及对其的识别 血栓形成中的底物，（b）硫醇异构酶影响硫醇的确切证据 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，（d） 临床实践中的硫醇异构酶靶向试剂的引入。在接下来的7年中，我们 将评估硫醇异构酶在与败血症相关的血栓形成中的作用，可遗传 高凝状态，抗磷脂综合征和癌症。因此，这个程序将 探讨硫醇异构酶如何启动血栓形成的基本生物学和 确定他们参与的血栓性疾病。

项目成果

Route exploration and synthesis of the reported pyridone-based PDI inhibitor STK076545.

• DOI: 10.1039/d0ob01205j
• 发表时间: 2020-09-14
• 期刊: Organic & biomolecular chemistry
• 影响因子: 3.2
• 作者: Greve E;Lindeman SV;Scartelli C;Lin L;Flaumenhaft R;Dockendorff C
• 通讯作者: Dockendorff C

The life cycle of platelet granules.

• DOI: 10.12688/f1000research.13283.1
• 发表时间: 2018
• 期刊: F1000Research
• 作者: Sharda A;Flaumenhaft R
• 通讯作者: Flaumenhaft R

Advances in vascular thiol isomerase function.

• DOI: 10.1097/moh.0000000000000362
• 发表时间: 2017-09
• 期刊: Current opinion in hematology
• 影响因子: 3.2
• 作者: Flaumenhaft R

PIEZO1 mediates a mechanothrombotic pathway in diabetes.

PIEZO1 介导糖尿病中的机械血栓形成途径。

• DOI: 10.1126/scitranslmed.abk1707
• 发表时间: 2022
• 期刊: Science translational medicine
• 影响因子: 17.1
• 作者: Zhu,Wandi;Guo,Shihui;Homilius,Max;Nsubuga,Cissy;Wright,ShaneH;Quan,Dajun;Kc,Ashmita;Eddy,SamuelS;Victorio,RachelleA;Beerens,Manu;Flaumenhaft,Robert;Deo,RahulC;MacRae,CalumA
• 通讯作者: MacRae,CalumA