Novel Therapeutics for Acquired Thrombotic Thrombocytopenic Purpura

获得性血栓性血小板减少性紫癜的新疗法

基本信息

批准号：
10231274
负责人：
X. Long Zheng
金额：
$ 45.77万
依托单位：
UNIVERSITY OF KANSAS MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-04-01 至 2023-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10231274
关键词：
ADP-ribosylation factor 6 Adhesions Affinity Allosteric Regulation Autoantibodies Binding Biological Assay Biology Blood Blood Platelets Blood capillaries C-terminal Calorimetry Cell Line Characteristics Cleaved cell Deuterium Distal Endocytosis Goals Hemostatic function Hospital Mortality Human Hydrogen Length Light Mass Spectrum Analysis Mediating Membrane Glycoproteins Mesentery Metalloproteases Microfluidics Molecular Mus Pathogenesis Patients Peptides Plasma Plasma Exchange Plasmapheresis Platelet aggregation Play Procedures Process Recombinants Regulation Relapse Role Site Site-Directed Mutagenesis Specificity Substrate Specificity Surface Plasmon Resonance Syndrome Thrombasthenia Thrombosis Thrombospondin 1 Thrombotic Thrombocytopenic Purpura Thrombus Titrations Treatment Efficacy Vascular Endothelium Whole Blood arteriole biochemical tools biophysical tools cellubrevin design experience ferric chloride human model induced pluripotent stem cell inhibitor/antagonist mouse model novel novel therapeutic intervention novel therapeutics prevent receptor receptor mediated endocytosis standard of care targeted delivery tool uptake vascular injury von Willebrand Factor

项目摘要

Project summary The overall goal of the proposed study is to understand the mechanism underlying allosteric regulation of ADAMTS13 function, to determine the therapeutic efficacy of rADAMTS13-loaded platelets in acquired thrombotic thrombocytopenic purpura (TTP), and to elucidate the mechanism underlying platelet uptake of rADAMTS13. In Aim 1, we will use the novel deuterium-hydrogen (HX) and mass spectrometry (MS) and other biophysical tools to determine the role of distal C-terminal domains in allosteric and pH-dependent regulation of ADAMTS13 function; In Aim 2, we will determine therapeutic efficacy of ADAMTS13-loaded platelets in murine and human models of acquired TTP; and In Aim 3, we will determine the mechanism underlying platelet endocytosis of ADAMTS13 by using β3-/-, arf6-/-, and VAMP3-/- mice. We believe that the results of the proposed study will shed new light on the fundamental biology of ADAMTS13, help to understand the pathogenesis of acquired TTP, and to develop a novel therapeutic strategy for this fatal syndrome and perhaps other arterial thrombotic disorders.

项目概要拟议研究的总体目标是了解变构调节的潜在机制 ADAMTS13 功能，以确定装载 rADAMTS13 的血小板对获得性血小板减少症的治疗效果血栓性血小板减少性紫癜（TTP），并阐明血小板摄取的机制 rADAMTS13。在目标 1 中，我们将使用新型氘氢 (HX) 和质谱 (MS) 等生物物理工具，用于确定远端 C 末端结构域在变构和 pH 依赖性调节中的作用 ADAMTS13 功能；在目标 2 中，我们将确定装载 ADAMTS13 的血小板对小鼠的治疗效果和获得性 TTP 的人体模型；在目标 3 中，我们将确定血小板的机制我们相信使用 β3-/-、arf6-/- 和 VAMP3-/- 小鼠对 ADAMTS13 的内吞作用。拟议的研究将为 ADAMTS13 的基础生物学提供新的线索，有助于理解获得性 TTP 的发病机制，并为这种致命综合征开发一种新的治疗策略，也许其他动脉血栓性疾病。