THE PROTEIN C RECEPTOR AND WEGENER'S VASCULOPATHY

描述：（改编自研究者摘要）：研究者 提出了一系列研究，将可溶性内皮蛋白C 受体（EPCR），蛋白C抗凝途径的成员， 韦格纳肉芽肿病，一种以肉芽肿为特征的自身免疫性疾病 炎症和坏死性血管炎。他们观察到可溶性EPCR 可以与活化的中性粒细胞结合，这种结合在很大程度上是由 蛋白酶-3（PR 3），韦格纳病中自身抗体（cANCA）的靶点 患者和β 2整合素。EPCR与细胞上或纯化的细胞中的PR 3结合 系统被cANCA抑制。一种抗β 2链的单克隆抗体， 白细胞粘附分子（CD 18）和针对独特α链的抗体 Mac-1（CD 11b）也阻断可溶性EPCR与活化的中性粒细胞的结合。 最后，可溶性EPCR可阻断中性粒细胞与TNF的紧密粘附 α-激活的内皮细胞。这些观察引出了他们的工作 假设PR 3与β 2整联蛋白的相互作用在 白细胞粘附和可溶性EPCR通过掩蔽关键位点来阻断该功能 在PR 3上。cANCA干扰可溶性EPCR与PR 3-β 2整联蛋白的结合 复合物，从而阻止EPCR的负调控功能。他们的 具体目标是研究结构-功能关系， 通过定义成对相互作用的EPCR-PR 3-β 2整联蛋白相互作用 参数以及这些复合物对中性粒细胞信号传导的影响， 粘附功能。具体目标是：1）表征可溶性 EPCR-PR 3结合复合物; 2）研究控制EPCR-PR 3结合复合物的成对相互作用。 可溶性EPCR-PR 3-β 2整联蛋白复合物的形成;和3）评估 cANCA对EPCR-PR 3-β 2整合素相互作用的影响， 中性粒细胞粘附他们的研究集中在可溶性EPCR如何影响 白细胞运输和cANCA在调节这一过程中的作用。结果 从这些研究将有助于确定新的机制， 韦格纳肉芽肿性血管炎中cANCA介导的内皮损伤在 另外，本研究结果也为今后的研究提供了基础 研究潜在的治疗靶点， 内皮损伤，特别是cANCA介导的血管炎。

DESCRIPTION: (Adapted from the Investigator's abstract): The investigators present a series of studies that link the soluble endothelial protein C receptor (EPCR), a member of the protein C anticoagulant pathway, with Wegener's granulomatosis, an autoimmune disease characterized by granulomatous inflammation and necrotizing vasculitis. They have observed that soluble EPCR can bind to activated neutrophils and this binding is mediated in large part by proteinase-3 (PR3), the target of the autoantibodies (cANCA) in Wegener's patients, and a beta2 integrin. EPCR binding to PR3 on cells or in purified systems is inhibited by cANCA. A monoclonal antibody to the beta2 chain of the leukocyte adhesion molecules (CD18) and an antibody to the unique alpha chain of Mac-1 (CD11b) also block binding of soluble EPCR to activated neutrophils. Finally, soluble EPCR can block tight adhesion of neutrophils to TNF alpha-activated endothelial cells. These observations elicit their working hypothesis that PR3 interaction with the beta2 integrin plays a role in leukocyte adhesion and soluble EPCR blocks this function by masking a key site on PR3. cANCA interferes with soluble EPCR binding to the PR3-beta2 integrin complex, thus preventing the negative regulatory function of EPCR. Their specific aims are to investigate the structure-function relationships of EPCR-PR3-beta2 integrin interactions by defining pair-wise interaction parameters and the influence of these complexes on neutrophil signaling and adhesion functions. The specific aims are to: 1) characterize the soluble EPCR-PR3 binding complex; 2) investigate the pair-wise interactions governing soluble EPCR-PR3-beta2 integrin complex formation; and 3) evaluate the influence of cANCA on the EPCR-PR3-beta2 integrin interaction with regard to neutrophil adhesion. Their studies focus on how soluble EPCR may influence leukocyte trafficking and the role of cANCA in modulating this process. Results from these studies will contribute to the identification of novel mechanisms of cANCA-mediated endothelial injury in vasculitis of Wegener's granulomatosis. In addition, the results will provide a foundation for future studies investigating potential therapeutic targets that modulate neutrophil-mediated endothelial injury, particularly for cANCA-mediated vasculitis.