Mechanism of action and therapeutic targeting of properdin in complement injury

描述（由申请人提供）：血浆蛋白properdin在半个多世纪前被发现，与补体激活的替代途径（AP）有关。虽然它最初被认为是AP补体的启动剂，但目前对properdin功能的看法是它作为AP C3转化酶C3bBb的稳定剂，在AP补体激活中起促进作用，但不是必不可少的作用。我们已经生成了初步数据，表明properdin对自体组织的AP补体激活至关重要，从而挑战了目前关于properdin功能的观点，并将其确定为补体损伤的潜在治疗靶点。在本研究中，我们将明确properdin在AP补体激活和组织损伤中的作用，并探索在补体依赖性疾病小鼠模型中抗properdin治疗的策略。我们的具体目标是：1。制备组织特异性properdin敲除小鼠和抗小鼠properdin抗体，测定properdin在体内的来源和周转。2. 目的：观察properdin在小鼠关节炎模型中的作用，评价抗properdin治疗关节炎的疗效；3.探讨properdin在非典型溶血性尿毒症综合征（aHUS）发病中的作用，并评价抗properdin治疗aHUS的疗效。这些研究将为properdin的作用和机制作用提供新的线索，并促进针对关节炎、aHUS和其他AP补体介导的病理的新型抗补体疗法的开发。

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. PUBLIC HEALTH RELEVANCE: This project studies the role of a protein called properdin in two immune-mediated diseases affecting the joints (arthritis) and the kidney (aHUS, for atypical hemolytic uremic syndrome). We will use the mouse as a model to test the hypothesis that properdin is involved in the pathogenesis of arthritis and aHUS and will develop monoclonal antibodies against properdin to treat these two diseases. These pre-clinical studies may lead to the development of anti-properdin agents as therapeutic drugs for human patients suffering from these conditions.