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PDI inhibition to prevent thrombosis in humans

PDI 抑制可预防人类血栓形成

基本信息

批准号：
8656770
负责人：
Bruce Furie
金额：
$ 57.62万
依托单位：
BETH ISRAEL DEACONESS MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
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/8656770
关键词：
Adult Animal Model Anticoagulants Antiphospholipid Antibodies Ascorbic Acid Aspirin Like Agents 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

项目摘要

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.

项目概述（见说明）：