BIOLOGY OF DECAY ACCELERATING FACTOR

描述：(改编自调查者摘要)：虽然补语 在宿主防御中起着至关重要的作用，激活补体是一把双刃剑 有可能对自身组织造成实质性损害的剑。 宿主组织避免补体介导的自体攻击的一种方法是 在其细胞表面表达特定的补体抑制蛋白。腐烂 加速因子(DAF，C：D55)是一种糖基磷脂酰肌醇 (GPI)-锚定的膜调节剂，可同时抑制经典和 补体激活的其他途径。DAF对人体的影响 红细胞在阵发性睡眠症发病机制中的作用 血红蛋白尿症(PNH)，一种疾病，其特征是对 受影响的红细胞对补体介导的裂解。人类DAF也被 作为一种潜在的治疗药物进行实验，以防止超急性 异种移植中的排斥反应。目的：评价DAF对脑损伤的保护作用。 在可能发生补体激活的病理过程中， 研究人员通过基因打靶获得了DAF基因敲除(KO)小鼠。在这 在研究中，他们建议使用这些小鼠来评估补体的参与 以及DAF在两种自身抗体介导的组织损伤模型中对其的调节： 自身免疫性溶血性贫血与抗肾小球肾炎。他们的中心 假说是膜补体调节蛋白如DAF 代表着决定是否以及在多大程度上 补体系统参与自身免疫组织损伤。具体目标 目的：1)确定DAF在补体介导的免疫反应中是否起到保护作用 免疫性溶血性贫血。他们将评估补体在 抗红细胞免疫球蛋白和免疫球蛋白诱导的小鼠免疫性溶血性贫血 确定DAF缺乏是否会加重疾病。DAF-、(23-和FCR-KO 并利用DAF/FCR双KO小鼠分析补体FCR的作用 和DAF在破坏自身抗体包被的红细胞方面。2)确定 DAF在抗肾小球基底膜中是否具有保护作用 (GBM)诱导的小鼠肾小球肾炎。通过使用DAF KO和DAI/FCR，DAF/C3 双KO小鼠，我们将确定抗GBM诱导的肾小球损伤是否 在DAF KO小鼠中加重以及是早期(C3a，C5a)还是晚期增加 (C5b-9)补体活动起作用。这些研究不仅将 确定DAF在自身免疫反应中的生理作用，但也将 阐明关于补体在自身免疫中的作用的争论 疾病。

DESCRIPTION: (Adapted from the Investigator's abstract): Although complement plays an essential role in host defense, activated complement is a double-edged sword that has the potential to inflict substantial damages to self-tissues. One way by which host tissues avoid complement mediated autologous attack is to express specific complement inhibiting proteins on their cell surface. Decay accelerating factor (DAF, C:D55) is a glycosylphosphatidylinositol (GPI)-anchored membrane regulator that inhibits both the classical and alternative pathways of complement activation. Deficiency of DAF on human erythrocytes contributes to the pathogenesis of paroxysmal nocturnal hemoglobinuria (PNH), a disease characterized by heightened sensitivity of affected erythrocytes to complement-mediated lysis. Human DAF has also been experimented on as a potential therapeutic agent to prevent hyperacute rejection in xenotransplantation. To evaluate the protective role of DAF in pathological processes where complement activation might occur, the investigators have generated DAF knockout (KO) mice by gene targeting. In this study, they propose to use these mice to evaluate the involvement of complement and its regulation by DAF in two models of autoantibody-mediated tissue damage: autoimmune hemolytic anemia and anti-GBM glomerulonephritis. Their central hypothesis is that membrane complement regulating proteins such as DAF represent an important factor in determining whether and to what degree the complement system is involved in autoimmune tissue damage. The specific aims are: 1) to determine if DAF offers a protective role in complement-mediated immune hemolytic anemia. They will assess the role of complement in anti-erythrocyte IgM- and IgG-induced murine immune hemolytic anemia and determine whether DAF-deficiency exacerbates the disease. DAF-, (23- and FcR-KO and DAF/FcR double KO mice will be used to dissect the roles of complement FcR and DAF in the destruction of autoantibody-coated erythrocytes. 2) to determine if DAF offers a protective role in anti-glomerular basement membrane (GBM)-induced murine glomerulonephritis. By using DAF KO and DAI /FcR, DAF/C3 double KO mice, we will determine if anti-GBM-induced glomerular injury is exacerbated in the DAF KO mice and whether increased early (C3a, C5a) or late (C5b-9) complement activity is responsible. These studies will not only establish a physiological role of DAF in autoimmune reactions but also will shed light on the debate concerning the role of complement in autoimmune diseases.