Novel Therapeutics for Acquired Thrombotic Thrombocytopenic Purpura

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，我们将确定加载 ADAMTS13 的血小板对小鼠的治疗效果 以及获得性 TTP 的人体模型；在目标 3 中，我们将确定血小板的潜在机制 使用 β3-/-、arf6-/- 和 VAMP3-/- 小鼠对 ADAMTS13 进行内吞作用。我们相信，这次调查的结果 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。

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.