PDI inhibition to prevent thrombosis in humans

PDI 抑制可预防人类血栓形成

• 批准号: 8532976
• 负责人: Bruce Furie
• 金额: $ 54.39万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-05-01 至 2017-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8532976
• 关键词: Adult; Animal Model; Anticoagulants; Antiphospholipid Antibodies; Ascorbic Acid; Aspirin Like Agents; Blood Clot; Blood Coagulation Factor; Blood Platelets; Blood Vessels; Blood coagulation; Cancer Patient; Cardiovascular system; Clinical Research; Clinical Trials; Complex; Development; Disease; Drug Kinetics; Endoplasmic Reticulum; Endothelial Cells; Epidemiologic Studies; Evaluation; Evaluation Studies; Event; Family; Fibrin; Fibrinolytic Agents; Flavonoids; Generations; Goals; Heparin; Human; Individual; Injury; Instruction; Isomerase; Laboratories; Lasers; Malignant Neoplasms; Membrane; Oral Administration; Oxidoreductase; Pathologic; Patients; Pattern; Pharmacodynamics; Phase II Clinical Trials; Placebo Control; Plasma; Platelet Activation; Platelet aggregation; Prevention; Protein Biosynthesis; Protein Disulfide Isomerase; Proteins; Quercetin; Randomized; Reducing diet; Role; Rutin; Series; Staging; Sulfhydryl Compounds; Surface; Thrombocytopenia; Thromboplastin; Thrombosis; Translating; Venous; Warfarin; clopidogrel; dietary supplements; dimer; high throughput screening; in vitro activity; in vivo; inhibitor/antagonist; member; mortality; mouse model; novel; novel strategies; prevent; prospective

PROJECT SUMMARY (See instructions): The management of thrombotic disorders relies on the pharmacological targeting of either platelets or clotting factors. Protein disulfide isomerase (PDI) is secreted by platelets and endothelial cells following activation and localizes to the membrane surface. Given the role of PDI in regulating both platelet accumulation and fibrin generation in vivo, we propose to evaluate PDI as an antithrombotic target. A high throughput compound screen recently identified quercetin-3-rutinoside and related flavonoids as potent inhibitors of PDI oxidoreductase activity in vitro and thrombosis formation in vivo in several animal models. Several large epidemiologic studies have shown that quercetin-rich diets reduce cardiovascular events in humans. Considering that quercetin is a widely available nutritional supplement, the goal of this project is to investigate the antithrombotic activity of quercetin in hypercoagulable conditions as a means of validating PDI as a pharmacologic target. The specific aims of this project are (1) to evaluate pharmacokinetics and pharmacodynamics of quercetin or isoquercetin with ascorbic acid as well as to investigate whether quercetin is reduces d-dimer levels in thrombotic condition characterized by endothelial activation (i.e. antiphospholipid antibodies); (2) to determine if quercetin prevents thrombosis in patients with high circulating tissue factor (i.e. cancer patients); and lastly, (3) to investigate whether quercetin can prevent thrombotic complications in a disorder characterized by pathologic platelet activation (i.e. heparin induced thrombocytopenia with thrombosis). By investigating quercetin in these different hypercoagulable conditions, we aim to translate recent laboratory observations directly into later stage clinical trials.

项目总结（见说明）： 血栓性疾病的管理依赖于血小板或凝血因子的药理学靶向。蛋白质二硫键异构酶（PDI）在活化后由血小板和内皮细胞分泌并定位于膜表面。鉴于PDI在体内调节血小板聚集和纤维蛋白生成中的作用，我们建议评估PDI作为抗血栓形成靶点。高通量化合物筛选最近鉴定了槲皮素-3-芸香糖苷和相关的黄酮类化合物作为体外PDI氧化还原酶活性和几种动物模型中体内血栓形成的有效抑制剂。 几项大型流行病学研究表明，富含槲皮素的饮食可以减少人类的心血管事件。考虑到槲皮素是一种广泛使用的营养补充剂，本项目的目标是研究槲皮素在高凝状态下的抗血栓形成活性，作为验证PDI作为药理学靶点的一种手段。本课题的具体目的是：（1）评价槲皮素或异槲皮素与抗坏血酸的药代动力学和药效学，并研究槲皮素是否能降低以内皮激活为特征的血栓性疾病中的D-二聚体水平（即抗磷脂抗体）;（2）确定槲皮素是否可预防高循环组织因子患者的血栓形成（即癌症患者）;最后，（3）研究槲皮素是否可以预防 以病理性血小板活化为特征的疾病中的血栓性并发症（即肝素诱导的血小板减少症伴血栓形成）。通过研究槲皮素在这些不同的高凝状态下，我们的目标是将最近的实验室观察结果直接转化为后期临床试验。