THE PROTEIN C RECEPTOR AND WEGENER'S VASCULOPATHY

描述：(改编自《调查员摘要》)：调查员 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，与 韦格纳肉芽肿，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，可溶的EPCR 可以与激活的中性粒细胞结合，这种结合在很大程度上是通过 蛋白水解酶-3(PR3)是韦格纳病自身抗体(CACA)的靶标 患者和β2整合素。EPCR与细胞上或纯化后的PR3结合 系统受到Canca的限制。抗猪传染性支气管炎病毒β2链的单抗 白细胞黏附分子(CD18)和一种独特的阿尔法链抗体 Mac-1(CD11b)还可阻断可溶性EPCR与激活的中性粒细胞的结合。 最后，可溶性内皮细胞聚合酶链式反应可以阻断中性粒细胞与肿瘤坏死因子的紧密黏附。 阿尔法激活的内皮细胞。这些观察启发了他们的工作 假设PR3与Beta2整合素相互作用在 白细胞黏附和可溶性EPCR通过掩蔽关键部位来阻断这一功能 在PR3上。CancA干扰可溶性EPCR与PR3-Beta2整合素的结合 复杂，从而阻止了EPCR的负调控功能。他们的 具体目的是研究结构与功能的关系。 通过定义成对相互作用实现EPCR-PR3-Beta2整合素相互作用 这些复合体的参数及其对中性粒细胞信号转导和 粘合功能。具体的目的是：1)表征可溶的 EPCR-PR3结合复合体；2)研究两两相互作用 可溶性EPCR-PR3-Beta2整合素复合体的形成；3)评价 CancA对EPCR-PR3-Beta2整合素相互作用的影响 中性粒细胞黏附。他们的研究集中在可溶的内质网聚合酶链式反应如何影响 白细胞贩运和Canca在调节这一过程中的作用。结果 这些研究将有助于识别新的机制。 韦格纳肉芽肿血管炎中癌基因介导的内皮损伤。在……里面 此外，研究结果还将为今后的研究提供基础 研究调节中性粒细胞介导的潜在治疗靶点 血管内皮损伤，尤其是肿瘤介导的血管炎。

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.