血管性血友病（VWD）是最常见的出血紊乱的原因，也会引发多种相关疾病。由于对血管性血友病因子（VWF）的结构和功能调控机制认识尚浅，VWD临床精准分型比较困难，且血浆置换和DDAVP等治疗手段缺乏靶向性和持续性。我们发现VWF的A1结构域两翼的短肽区域与A1结构域相互作用，且A1的活性与这两段短肽区域的长度成反比。我们假设在低剪切力环境下A1两翼的短肽区域结合A1抑制其活性，而在高剪切力环境下这种结合受损而导致A1发挥活性，称之为非连续性自抑制结构假说。围绕此假说，我们将利用氢氘交换质谱（HDX）和小鼠模型等手段，1）解析全长VWF结构域之间的相互作用和VWF活化时的构象变化，验证在全长VWF多聚体中非连续性自抑制结构模型，2）开发用于精准诊断VWD亚型的靶向抗体，3）探索利用该靶向抗体治疗VWD的可行性。这将有利于进一步认识VWF的结构与功能的关系并发展更安全有效的治疗VWD手段。

Von Willebrand Disease (VWD) is the most common bleeding disorder in the world, which may induce other diseases such as thrombosis, inflammation, multiple cardiovascular disease and cancers. Currently, the main management of VWD is plasma exchange and hormone therapy. These treatments are valid only in short-term and lack of persistence and targeting. One of the major difficulty attributes to these is the short in knowledge of the structure and function of von Willebrand factor, a huge glycoprotein in blood vessel. We have enriched experiences in studying the structure and interaction of huge protein complex using hydrogen-deuterium exchange mass spectrometer (HDX). In this study, our goals include: 1) explore the structure of multimeric VWF, complete the autoinhibitory module of VWF self-inhibitory mechanism, demonstrate the effect of shear stress in VWF’s activity; 2) develop novel antibodies targeting the active and inactive form of VWF, improve the accurate diagnosis of VWD subtypes; 3) test the possibility of using these antibodies to treat VWD, improve the efficacy and safety of VWD treatment.