Pathogenesis of Thrombotic Microangiopathy

 描述(申请人提供)：血浆ADAMTS13活性缺乏，遗传性或获得性，导致血栓性血小板减少性紫癜(TTP)。然而，TTP的发病机制和触发事件尚不完全清楚。新出现的数据表明，补体激活可能与溶血性尿毒症综合征(HUS)和TTP有关。在目标1中，我们建议确定CFH在流动条件下对ADAMTS13介导的VWF蛋白降解及其黏附功能的影响。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的激活/失活。在目标2中，我们将在小鼠模型中确定CFH的遗传或获得性缺陷在获得性TTP(带有抑制剂)的发生、发展和结局中的作用。在目标3中，我们建议确定服用抑制剂的获得性TTP患者补体成分和调节因子基因突变的发生率。我们的假设是，通过单独或与rADAMTS13联合使用抗补体治疗来抑制补体激活，可以更好地防止疾病病理的发生和发展，或加速其恢复。这项研究的结果将促进我们对CFH在生理切应力下调节VWF功能的基础作用的理解，为获得性TTP的机制提供新的线索，并为测试新疗法的疗效提供宝贵的工具。

 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.