Novel Therapeutics for Acquired Thrombotic Thrombocytopenic Purpura

项目总结 拟议研究的总体目标是了解变构调节的潜在机制。 ADAMTS13功能，评价rADAMTS13负载血小板治疗获得性血液病的疗效 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，我们将使用新型的重氢(HX)和质谱学(MS)等 生物物理工具，以确定远端C-末端结构域在变构和pH依赖的调节中的作用 ADAMTS13的功能；在目标2中，我们将确定ADAMTS13负载的血小板在小鼠体内的治疗效果 和获得性TTP的人体模型；在目标3中，我们将确定血小板的潜在机制 β3-/-、ARF6-/-和VAMP3-/-小鼠对ADAMTS13的内吞作用我们相信，这一结果 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，并开发一种新的治疗策略来治疗这种致命的综合征，并可能 其他动脉血栓性疾病。

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.