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: 8843931
• 负责人: Bruce Furie
• 金额: $ 223万
• 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 2016-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8843931
• 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）： 这项在血栓和止血疾病中的转化研究中心的应用描述了开发新型抗血栓形成剂的研究。组件项目将蛋白质二硫化物异构酶（PDL）作为抗血栓形成靶标，使用等喹啉，槲皮素3-鲁丁苷和槲皮素作为PDL的抑制剂。在项目＃1中，与芭芭拉·弗里（Barbara Furie）博士和明东·黄（Mingdong Huang）博士的布鲁斯·弗里（Bruce Furie）博士探索了PDL参与血栓产生的机制，并将在体内血栓形成模型中测试PDL抑制剂是否可以防止小鼠血栓形成。 Huang博士将解决有或没有结合PDL抑制剂的PDL的晶体结构。在项目＃2中，罗伯特·弗拉曼哈夫特（Robert Flaumenhaft）博士和纳塔利娅·贝洛娃（Natalia Beglova）博士将在广阔研究所寻找更有效的PDL抑制剂。 PDL结构域将被表达，并与NMR光谱检查检查的小分子PDL抑制剂的相互作用。新的配体将是由广泛研究所的化学家合成的，随后进行了测试。该项目将在这类新的抗血栓形成类别中扩大可用于评估的PDL配体的数量。在项目＃3中，与Donna Neuberg博士的Jeffrey Zwicker博士将探索槲皮素和异喹啉在人类中的抗强化特性，这是批准人使用的代理商。将在存在和不存在抗坏血酸的情况下对槲皮素和等喹啉进行药代动力学研究，以确定最佳递送。将评估PDL抑制剂在三个单独的人类研究中的有效性：癌症患者的血栓栓塞事件；肝素引起的血小板减少症和血栓形成；抗磷脂综合征。此TRC-THD将包括四个核心，这些核心将为整个程序提供支持。行政核心（核心A）将由布鲁斯·弗里（Bruce Furie）博士指导，并将协调这三个项目的活动。插入式显微镜和动物核心（Core B）将由Barbara C. Furie博士指导。分子和结构生物学核心（核心C）将由Mingdong Huang博士和Natalia Beglova博士共同指导。翻译技能开发核心（核心D）将由肯尼斯·鲍尔（Kenneth Bauer）博士指导。该中心将致力于开发针对抗血小板和抗凝特性的PDL的新一类抗血栓形剂。