The Biology of VWF Self-Association

VWF 自关联的生物学

• 批准号: 9336492
• 负责人: DOMINIC W. CHUNG
• 金额: $ 56.68万
• 依托单位: BLOODWORKS
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-15 至 2017-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9336492
• 关键词: Adhesions; Adhesives; Apolipoprotein A-I; Area; Atherosclerosis; Attenuated; Binding; Biology; Blood Coagulation Disorders; Blood Platelets; Blood Vessels; Blood flow; Caliber; Cardiovascular system; Cleaved cell; Disease; Disease Outcome; Enzymes; Functional disorder; Glycoproteins; Health; Hemorrhage; Hemostatic function; High Density Lipoproteins; Human Pathology; Infarction; Injury; Length; Lipoprotein (a); Lipoproteins; Liquid substance; Malaria; Mediating; Metalloproteases; Microvascular Dysfunction; Organ; Outcome; Pathologic; Pathology; Peptide Hydrolases; Peptide Mapping; Phase; Physiological; Plasma; Play; Polymers; Process; Property; Proteins; Resistance; Role; Sepsis; Sepsis Syndrome; Severities; Sickle Cell Anemia; Site; Surface; Syndrome; Systemic disease; Testing; Thrombosis; Thrombotic Thrombocytopenic Purpura; Thrombus; Tissues; Variant; Work; base; hydrodynamic flow; improved; improved outcome; insight; microvascular pathology; molecular size; mouse model; novel; novel strategies; prevent; protein function; response; shear stress; von Willebrand Disease; von Willebrand Factor

 DESCRIPTION (provided by applicant): von Willebrand factor (VWF) is a multimeric glycoprotein in plasma that plays an important role in hemostasis by mediating platelet binding to sites of vascular injury. In recent studies, VWF has also been implicated in microvascular dysfunction and occlusion, in part because of its unique ability to sel�associate and form hyper-adhesive strands of enormous sizes attached to the endothelial surface in response to hydrodynamic forces, including shear stress and elongation flow. When these strands are not removed by the metalloprotease ADAMTS13 in plasma, they bind platelets efficiently, and the accumulation of VWF‐platelet thrombi leads to vessel occlusion, tissue infarction, and organ dysfunction. We recently discovered that high density lipoprotein (HDL), a well‐known cardioprotective lipoprotein in plasma, and its major component protein apolipoprotein (Apo)A‐I, can attenuate the extent of VWF self‐association, and ultimately the severity of thrombotic complications in the vasculature. These studies unveiled a novel antithrombotic property of HDL/ApoA‐I, which we hypothesize is very important in diseases characterized by microvascular occlusion. In this application, we will focus on the mechanism of VWF self‐association, how VWF interacts with HDL/ApoA‐I, and the physiologic impact of the HDL-VWF interaction. In Specific Aim 1, we will identify the VWF self‐ association site exposed by hydrodynamic forces by peptide mapping and use of VWF variants. In Specific Aim 2, we will determine the effect of VWF self‐association on ADAMTS13‐mediated cleavage under shear stress, and assess the role of HDL in ADAMTS13‐mediated cleavage of VWF. In Specific Aim 3, we will evaluate in mouse models of TTP and sepsis whether the outcome and disease parameters are worsened by HDL deficiency or improved by HDL treatment. Successful completion of these aims will provide an improved understanding of the basic mechanism of VWF self‐association, how this process can be regulated, and how this information can be used to develop new approaches to treat systemic diseases caused by dysregulation of VWF self‐association.

 描述（由适用提供）：von Willebrand因子（VWF）是血浆中的一种多层糖蛋白，通过介导血小板结合血管损伤部位，在止血中起重要作用。在最近的研究中，VWF在微血管功能障碍和闭塞中也被浸渍，部分原因是它具有独特的SEL和结合能力，并形成了巨大大小的高粘连链，这些大小附着在内皮表面上，响应于水动力学，包括剪切应力和拉长流动。当金属蛋白酶ADAMTS13在等离子体中未去除这些链时，它们会有效结合血小板，并且VWF-植物性血栓的积累会导致血管闭塞，组织违规和器官功能障碍。我们最近发现，高密度脂蛋白（HDL）是血浆中众所周知的心脏保护脂蛋白及其主要成分蛋白载脂蛋白（APO）A-I，可以减轻VWF自我关联的程度，最终导致血管造血管并发症的严重性。 这些研究揭示了HDL/APOA -I的新型抗血栓性特性，我们认为这对于以微血管闭塞为特征的疾病非常重要。在此应用程序中，我们将重点关注VWF自我关联的机制，VWF如何与HDL/APOA-I相互作用以及HDL-VWF相互作用的物理影响。在特定目标1中，我们将确定通过肽映射和使用VWF变体所暴露的VWF自我关联位点。在特定的目标2中，我们将确定剪切应力下的VWF自我相互交流对ADAMTS13介导的裂解的影响，并评估HDL在ADAMTS13介导的VWF裂解中的作用。在特定的目标3中，我们将在TTP和败血症的小鼠模型中评估，无论结果和疾病参数因HDL缺乏而恶化还是通过HDL治疗改善。这些目标的成功完成将提供对VWF自我关联的基本机制，如何调节该过程的基本机制以及如何使用该信息来开发新方法来治疗因VWF自我关联失调引起的全身性疾病的方法。