Mechanism of action and therapeutic targeting of properdin in complement injury

描述(由申请人提供)：半个多世纪前发现的血浆蛋白备解素与补体激活的替代途径(AP)有关。虽然最初被认为是AP补体的起始者，但目前对备解素功能的看法是，它作为AP C3转换酶C3bBb的稳定剂，在AP补体激活中起到促进但不是必需的作用。我们已经产生的初步数据表明，备解素对自体组织上的AP补体激活至关重要，从而挑战了目前对备解素功能的看法，并将其确定为补体损伤的潜在治疗靶点。在这项建议中，我们将确定备解素在AP补体激活和组织损伤中的作用，并探索在补体依赖型疾病小鼠模型中抗备解素治疗的策略。我们的具体目标是：1.制备组织特异性的备解素基因敲除小鼠和抗小鼠备解素抗体，并确定备解素在体内的来源和转运。2.检测备解素在小鼠关节炎模型中的作用，评价抗备解素治疗关节炎的疗效：3.检测备解素在非典型溶血性尿毒症综合征(AHUS)发病机制中的作用，评价抗备解素治疗在aHUS中的作用。这些研究将阐明备解素的作用和机制，并有助于开发针对关节炎、aHUS和其他AP补体介导的病理的新型抗补体疗法。

DESCRIPTION (provided by applicant): The plasma protein properdin was discovered more than a half-century ago in connection with the alternative pathway (AP) of complement activation. Although it was initially regarded as an initiator of the AP complement, the currently held view of properdin function is that it acts as a stabilizer of the AP C3 convertase C3bBb, playing a facilitating but not essential role in AP complement activation. We have generated preliminary data to show that properdin is critical for AP complement activation on autologous tissues, thus challenging the present view on properdin function and identifying it as a potential therapeutic target in complement injury. In this proposal, we will define the role of properdin in AP complement activation and tissue injury and explore the strategy of anti-properdin therapy in murine models of complement-dependent disease. Our specific aims are: 1. To generate tissue-specific properdin knockout mice and anti-mouse properdin antibodies and determine the source and turnover of properdin in vivo. 2. To test the role of properdin in murine models of arthritis and evaluate the efficacy of anti-properdin therapy in arthritis; 3.To test the role of properdin in the pathogenesis of atypical hemolytic uremic syndrome (aHUS) and evaluate the efficacy of anti-properdin therapy in aHUS. These studies will shed new light on the role and mechanism action of properdin and facilitate the development of novel anti-complement therapies for arthritis, aHUS and other AP complement-mediated pathologies.