Proteases in the Pathogenesis and Treatment of Thrombosis

描述（由申请人提供）： 华盛顿大学血栓和止血疾病转化研究中心致力于了解蛋白酶在血栓形成病理生理学中的作用，血栓形成是许多常见疾病的严重并发症。该中心将采用互动的多学科方法，涉及5个项目和4个核心单元，专注于微血管和大血管血栓形成。项目1将描述ADAMTS13底物特异性的分子基础，开发优化的检测方法以研究ADAMTS13缺陷在血栓性微血管病中的作用，并评估预防血栓性血小板减少性紫癜复发的治疗方法。项目2将采用基因组测序来鉴定导致血栓性微血管病（包括非典型溶血性尿毒症综合征、先兆子痫和自身免疫性疾病）的补体调节和止血缺陷，并确定这些突变导致疾病的生化机制。项目3将设计一种改进的凝血酶变体，其对蛋白C具有特异性活性，以优化其抗凝血和抗炎活性，用于治疗血栓形成和败血症。项目4将描述新的组织因子抑制剂，并评估其在血栓形成、脓毒症、HUS和癌症进展的动物模型中的疗效。项目5将开发一流的基于纳米颗粒的直接凝血酶抑制剂，具有双重抗血小板活性，并对其进行评估 用于血栓的治疗性溶解和磁共振成像。这些项目依赖于核心单位进行后勤和监督（核心A），患者招募和样本库（核心C）以及基因组分析（核心D）。新研究者将接受转化和临床研究（核心B）方面的指导和培训。该中心的实验方法包括基本的分子和最先进的遗传方法，动物模型，信息患者的生化和生理研究，以及评估基于机制的治疗方法的临床研究。这些项目将促进基础研究发现迅速转化为临床护理创新。

DESCRIPTION (provided by applicant): The Translational Research Center in Thrombotic and Hemostatic Disorders at Washington University is dedicated to understanding the role of proteases in the pathophysiology of thrombosis, which is a serious complication of many common diseases. This Center will pursue an interactive, multi-disciplinary approach involving 5 Projects and 4 Core Units that focus on microvascular and macrovascular thrombosis. Project 1 will characterize the molecular basis of ADAMTS13 substrate specificity, develop optimized assays to investigate the role of ADAMTS13 deficiency in thrombotic microangiopathy, and evaluate treatments to prevent relapses in thrombotic thrombocytopenic purpura. Project 2 will employ genomic sequencing to identify defects in complement regulation and hemostasis that cause thrombotic microangiopathy, including atypical hemolytic uremic syndrome, preeclampsia, and autoimmune disorders, and determine the biochemical mechanism by which these mutations cause disease. Project 3 will engineer an improved thrombin variant with exclusive activity toward protein C to optimize its anticoagulant and anti-inflammatory activity for treating thrombosis and sepsis. Project 4 will characterize new inhibitors of tissue factor and evaluate their efficacy in animal models of thrombosis, sepsis, HUS, and cancer progression. Project 5 will develop a first-in-class nanoparticle-based direct thrombin inhibitor with dual antiplatelet activity, and evaluate it for therapeutic dissolution and magnetic resonance imaging of thrombi. These projects rely on Core Units for logistics and oversight (Core A), patient enrollment and sample banking (Core C), and genomic analysis (Core D). New investigators will receive mentoring and training in translational and clinical research (Core B). The experimental approaches of the Center encompass basic molecular and state-of-the-art genetic methods, animal models, and biochemical and physiological studies of informative patients, as well as clinical studies to assess mechanism-based therapeutic approaches. These projects will facilitate the rapid translation of basic research discoveries into innovations in clinical care.