Protein disulfide isomerases: A new class of antithrombotic targets

蛋白质二硫键异构酶：一类新的抗血栓靶点

• 批准号: 8532972
• 负责人: Bruce Furie
• 金额: $ 211.36万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-01 至 2017-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8532972
• 关键词: Address; Animals; Anticoagulants; Antiphospholipid Syndrome; Ascorbic Acid; Award; Binding Proteins; Center for Translational Science Activities; Clinical; Data; Deep Vein Thrombosis; Development; Disease; Drug Industry; Drug Kinetics; Effectiveness; Electron Transport Pathway; Evaluation; Event; Fibrinolytic Agents; Funding; Generations; Goals; Grant; Hemostatic Agents; Heparin; Human; Institutes; Intellectual Property; Isomerase; Knowledge; Laboratories; Laboratory Finding; Lead; Ligands; Malignant Neoplasms; Modeling; Molecular Biology; Mus; Myocardial Infarction; NMR Spectroscopy; Outcome; Pathway interactions; Patients; Pharmacologic Substance; Property; Protein Disulfide Isomerase; Public Health; Pulmonary Embolism; Quercetin; Research; Resources; Role; Rutin; Stroke; Structure; Sulfhydryl Compounds; Testing; Therapeutic Agents; Thrombocytopenia; Thromboembolism; Thrombosis; Thrombus; Translating; United States; United States National Institutes of Health; Venous; Work; abstracting; design; drug development; in vivo; inhibitor/antagonist; interest; intravital microscopy; mortality; multidisciplinary; novel; prevent; programs; skills; small molecule; structural biology

DESCRIPTION (provided by applicant): This application for a Translational Research Center in Thrombotic and Hemostatic Disorders describes research to develop a novel class of antithrombotic agents. Component projects explore protein disulfide isomerase (PDl) as an antithrombotic target using isoquercetin, quercetin 3-rutinoside and quercetin as inhibitors of PDl. In Project #1, Dr. Bruce Furie, with Dr. Barbara Furie and Dr. Mingdong Huang, explore the mechanism by which PDl participates in thrombus generation and will test in vivo thrombosis models whether PDl inhibitor can prevent thrombosis in mice. Dr. Huang will solve the crystal structure of PDl with and without a bound PDl inhibitor. In Project #2, Dr. Robert Flaumenhaft and Dr. Natalia Beglova will search for more potent PDl inhibitors at the Broad Institute. PDl domains will be expressed and their interaction with small molecule PDl inhibitors examined by NMR spectroscopy. New ligands will be designed, synthesized by chemists at the Broad Institute and subsequently tested. This project will expand the number of PDl ligands available for evaluation in this new class of antithrombotics. In Project #3, Dr. Jeffrey Zwicker, with Dr. Donna Neuberg, will explore the antithrombotic properties of quercetin and isoquercetin in humans, agents approved for human use. A pharmacokinetic study with quercetin and isoquercetin in the presence and absence of ascorbic acid will be performed to determine optimal delivery. The effectiveness of the PDl inhibitor in three separate human studies will be evaluated: thromboembolic events in patients with cancer; heparin-induced thrombocytopenia and thrombosis; anti-phospholipid syndrome. This TRC-THD will include four cores that will provide support to the overall program. The Administrative Core (Core A) will be directed by Dr. Bruce Furie, and will coordinate the activities of the three projects. The Intravital Microscopy and Animal Core (Core B) will be directed by Dr. Barbara C. Furie. The Molecular and Structural Biology core (Core C) will be co-directed by Dr. Mingdong Huang and Dr. Natalia Beglova. The Translational Skills Development Core (Core D) will be directed by Dr. Kenneth Bauer. The Center will work to develop a new class of antithrombotic agents directed against PDl with both antiplatelet and anticoagulant properties.

描述（由申请人提供）： 血栓和止血疾病转化研究中心的申请描述了开发一类新型抗血栓药物的研究。组成项目使用异槲皮素、槲皮素3-芸香糖苷和槲皮素作为roi的抑制剂来探索蛋白质二硫键异构酶（roi）作为抗血栓形成靶标。在项目#1中，布鲁斯福瑞博士与芭芭拉福瑞博士和黄明东博士一起探索了PD 1参与血栓生成的机制，并将在体内血栓形成模型中测试PD 1抑制剂是否可以预防小鼠中的血栓形成。Huang博士将解决具有和不具有结合的PD 1抑制剂的PD 1的晶体结构。在项目#2中，Robert Flaumenhaft博士和娜塔莉亚Beglova博士将在布罗德研究所寻找更有效的PD 1抑制剂。PD 1结构域将被表达，并且它们与小分子PD 1抑制剂的相互作用通过NMR光谱学检查。新的配体将由布罗德研究所的化学家设计、合成，随后进行测试。该项目将扩大可用于评估这类新的抗血栓药物的PD 1配体的数量。在项目#3中，Jeffrey Zwicker博士和Donna Neuberg博士将探索槲皮素和异槲皮素在人体中的抗血栓形成特性，这些药物已被批准用于人体。将在存在和不存在抗坏血酸的情况下进行槲皮素和异槲皮素的药代动力学研究，以确定最佳递送。将评估PD 1抑制剂在三个单独的人类研究中的有效性：癌症患者中的血栓栓塞事件;肝素诱导的血小板减少症和血栓形成;抗磷脂综合征。该TRC-THD将包括四个核心，为整个计划提供支持。行政核心（核心A）将由布鲁斯富里博士领导，并将协调三个项目的活动。活体显微镜检查和动物核心（核心B）将由Dr. Barbara C指导。复仇女神分子和结构生物学核心（核心C）将由黄明东博士和娜塔莉亚贝格洛娃博士共同指导。翻译技能发展核心（核心D）将由Kenneth Bauer博士指导。该中心将致力于开发一类针对PDl的新型抗血栓药物，具有抗血小板和抗凝剂特性。