Pathogenesis of Thrombotic Microangiopathy

血栓性微血管病的发病机制

基本信息

批准号：
9139498
负责人：
X. Long Zheng
金额：
$ 45.54万
依托单位：
UNIVERSITY OF ALABAMA AT BIRMINGHAM
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-09-14 至 2019-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9139498
关键词：
Adhesives Affect Age Amino Acids Antibodies Binding Binding Sites Biological Assay Biological Process Blood Circulation Blood Coagulation Disorders Blood capillaries C-terminal Cleaved cell Clinical Code Complement Complement 3b Complement Activation Complement Factor H Coupled Data Defect Deuterium Development Disease Disease Progression Endothelial Cells Enzyme-Linked Immunosorbent Assay Event F8 gene Factor VIII Fibrinogen Genes Genetic Genetic Polymorphism Health Hemolytic-Uremic Syndrome Hemostatic function Histology Human Hydrogen Immunohistochemistry Inherited Investigation Kinetics Laboratories Lead Light Liquid substance Mass Spectrum Analysis Mediating Metalloproteases Monoclonal Antibodies Mus Mutate Mutation Organ Outcome Pathogenesis Pathology Patients Physiological Plasma Platelet Glycoproteins Positioning Attribute Predisposition Prevalence Prevention Process Proteolysis Proteolytic Processing Reaction Recombinants Recovery Regulation Resolution Role Serine Protease Syndrome Testing Thrombosis Thrombotic Thrombocytopenic Purpura Thrombus Titrations Transgenic Mice Uncertainty Wild Type Mouse arteriole capillary clinical phenotype efficacy testing experience in vivo inhibitor/antagonist mouse model mutant novel therapeutics prevent sex shear stress tool von Willebrand Disease von Willebrand Factor

项目摘要

DESCRIPTION (provided by applicant): Deficiency of plasma ADAMTS13 activity, either hereditary or acquired, causes thrombotic thrombocytopenic purpura (TTP). However, the triggering events and mechanisms underlying the pathogenesis of TTP are not fully understood. Emerging data suggest that complement activation may be associated with both hemolytic uremic syndrome (HUS) and TTP. In Aim 1, we propose to determine the effects of CFH on ADAMTS13- mediated VWF proteolysis and its adhesive function under flow. We will also determine the kinetics and mechanism of such interactions and how such an interaction affects complement activation/inactivation. In Aim 2, we will determine the role of genetic or acquired deficiency of CFH on the occurrence, progression, and outcome of acquired TTP (with inhibitors) in murine models. In Aim 3, we propose to determine the prevalence of mutations in genes in complement components and regulators in patients with acquired TTP patients with inhibitors. We pursue the hypothesis that by inhibiting complement activation with anti-complement therapy either alone or in combination with rADAMTS13 one can better prevent the onset and progression of the disease pathology or accelerate its recovery. The results of the proposed study will advance our understanding of the fundamental role of CFH in regulation of VWF function under physiological shear stress, shed new light on the mechanisms of acquired TTP, and provide invaluable tools for testing the efficacy of novel therapeutics.

描述（由适用提供）：遗传性或获得的等离子体ADAMTS13活性的缺乏会导致血小板性血小板减少性紫癜（TTP）。但是，尚未完全了解TTP发病机理的触发事件和机制。新兴数据表明，完成激活可能与溶血性尿毒症综合征（HUS）和TTP均相关。在AIM 1中，我们建议确定CFH对ADAMTS13-介导的VWF蛋白水解及其在流动下的粘附功能的影响。我们还将确定这种相互作用的动力学和机制，以及这种相互作用如何影响补体激活/失活。在AIM 2中，我们将确定CFH遗传或获得性缺乏在鼠模型中获得的TTP（带有抑制剂）的发生，进展和结果的作用。在AIM 3中，我们建议确定获得抑制剂TTP患者的完成成分和调节剂中基因突变的普遍性。我们提出这样的假设，即通过抑制单独或与RadAmts13结合使用抗补充疗法的完成激活，可以更好地防止疾病病理学的发作和进展或加速其康复。拟议的研究的结果将促进我们对CFH在生理剪切应力下调节VWF功能的基本作用的理解，对获得的TTP的机制有了新的启示，并为测试新型治疗的有效性提供了宝贵的工具。