Novel Therapeutics for Acquired Thrombotic Thrombocytopenic Purpura

项目摘要 这项研究的总体目标是了解变构调节的机制， ADAMTS 13功能，以确定负载rADAMTS 13的血小板在获得性血小板减少性紫癜中的治疗功效。 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，我们将使用新的氘-氢（HX）和质谱（MS）等 生物物理工具，以确定远端C-末端结构域在变构和pH依赖性调节中的作用， 在目的2中，我们将确定负载ADAMTS 13的血小板在小鼠中的治疗功效。 和获得性TTP的人类模型;在目标3中，我们将确定血小板 通过使用β3-/-、arf 6-/-和VAMP 3-/-小鼠观察ADAMTS 13的内吞作用。我们认为， 这项研究将为ADAMTS 13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，这种致命的综合征，也许 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.