PDI inhibition to prevent thrombosis in humans

PDI 抑制可预防人类血栓形成

• 批准号: 8401641
• 负责人: Bruce Furie
• 金额: $ 61.41万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8401641
• 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.

项目摘要（参见说明）： 血栓性疾病的治疗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) 由血小板和内皮细胞激活后分泌，并定位于膜表面。鉴于 PDI 在调节体内血小板积累和纤维蛋白生成中的作用，我们建议将 PDI 作为抗血栓靶点进行评估。最近的一项高通量化合物筛选发现，槲皮素-3-芸香苷和相关黄酮类化合物是体外 PDI 氧化还原酶活性和多种动物模型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心血管事件。考虑到槲皮素是一种广泛使用的营养补充剂，该项目的目标是研究槲皮素在高凝状态下的抗血栓活性，作为验证 PDI 作为药理学靶点的手段。该项目的具体目标是（1）评估槲皮素或异槲皮素与抗坏血酸的药代动力学和药效学，以及研究槲皮素是否可以降低以内皮激活为特征的血栓性疾病（即抗磷脂抗体）中的d-二聚体水平； (2) 确定槲皮素是否可以预防高循环组织因子患者（即癌症患者）的血栓形成；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并发症（即肝素诱导的血小板减少伴血栓形成）。通过研究槲皮素在这些不同的高凝状态下的作用，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。