Proteases in the Pathogenesis and Treatment of Thrombosis

蛋白酶在血栓形成的发病机制和治疗中的作用

• 批准号: 8840626
• 负责人: J Evan Sadler
• 金额: $ 175.04万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-05-01 至 2016-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8840626
• 关键词: Animal Model; Anti-Inflammatory Agents; Anti-inflammatory; Anticoagulants; Atherosclerosis; Autoimmune Diseases; Basic Science; Biochemical; Biological Assay; Center for Translational Science Activities; Clinical; Clinical Research; Complement; Complication; Defect; Diabetes Mellitus; Disease; Engineering; Enrollment; Event; Functional disorder; Genetic; Genomics; Goals; Health; Hematopoietic stem cells; Hemolytic-Uremic Syndrome; Hemostatic Agents; Hemostatic function; Image; Infection; Inherited; Knowledge; Laboratories; Life; Logistics; Magnetic Resonance Imaging; Malignant Neoplasms; Mentors; Methods; Molecular; Molecular Genetics; Pathogenesis; Patients; Peptide Hydrolases; Physiological; Population; Pre-Eclampsia; Predisposition; Protein C; Regulation; Relapse; Research Personnel; Risk Factors; Role; Sampling; Scientist; Sepsis; Substrate Specificity; Systemic Lupus Erythematosus; Therapeutic; Thrombin; Thromboplastin; Thrombosis; Thrombotic Thrombocytopenic Purpura; Thrombus; Training; Translational Research; Translations; Universities; Variant; Venous; Washington; abstracting; base; clinical care; disease-causing mutation; improved; inhibitor/antagonist; innovation; nanoparticle; prevent; tumor progression

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.

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，血栓是许多常见疾病的严重并发症。该中心将采用互动、多学科的方法，涉及 5 个项目和 4 个核心单位，重点关注微血管和大血管血栓形成。项目 1 将表征 ADAMTS13 底物特异性的分子基础，开发优化的检测方法来研究 ADAMTS13 缺乏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将利用基因组测序来识别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，并确定这些突变引起疾病的生化机制。项目 3 将设计一种改进的凝血酶变体，该变体对蛋白 C 具有独特的活性，以优化其抗凝和抗炎活性，用于治疗血栓形成和败血症。项目 4 将表征新型组织因子抑制剂，并评估其在血栓形成、脓毒症、HUS 和癌症进展动物模型中的功效。项目5将开发一种首创的基于纳米颗粒的具有双重抗血小板活性的直接凝血酶抑制剂，并对其进行评估 用于血栓的治疗溶解和磁共振成像。这些项目依赖于物流和监督（核心 A）、患者登记和样本库（核心 C）以及基因组分析（核心 D）的核心单元。新研究人员将接受转化和临床研究方面的指导和培训（核心 B）。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、信息丰富的患者的生化和生理学研究，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快速转化为临床护理创新。