Mechanism of action and therapeutic targeting of properdin in complement injury

描述（由申请人提供）：血浆蛋白备解素在半个多世纪前被发现与补体激活的旁路途径（AP）有关。虽然它最初被认为是AP补体的起始物，但目前对备解素功能的看法是它作为AP C3转化酶C3 bBb的稳定剂，在AP补体活化中起促进作用但不是必需的作用。我们已经产生了初步的数据表明，备解素是AP补体激活自体组织的关键，从而挑战了目前的观点备解素功能，并确定其作为一个潜在的治疗靶点在补体损伤。在本研究中，我们将明确备解素在AP补体激活和组织损伤中的作用，并探索在补体依赖性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.制备组织特异性备解素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周转。2.探讨备解素在小鼠关节炎模型中的作用及抗备解素治疗的疗效; 3.探讨备解素在非典型溶血性尿毒症综合征（aHUS）发病中的作用及抗备解素治疗阿胡斯的疗效。这些研究将为备解素的作用和机制作用提供新的线索，并促进针对关节炎、阿胡斯和其他AP补体介导的病理的新型抗补体疗法的开发。 公共卫生相关性：该项目研究了一种名为备解素的蛋白质在影响关节（关节炎）和肾脏（阿胡斯，非典型溶血性尿毒症综合征）的两种免疫介导疾病中的作用。我们将使用小鼠作为模型来测试备解素参与关节炎和阿胡斯的发病机制的假设，并将开发针对备解素的单克隆抗体来治疗这两种疾病。这些临床前研究可能导致开发抗备解素剂作为患有这些病症的人类患者的治疗药物。

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.