The blockade of neuropilin-2 / plexin A2 as therapeutic principle in arthritis

阻断 Neuropilin-2/plexin A2 作为关节炎的治疗原则

• 批准号: 163601529
• 负责人: Professor Dr. Rainer H. Straub
• 金额: --
• 依托单位: Klinik und Poliklinik für Innere Medizin I
• 依托单位国家: 德国
• 项目类别: Research Units
• 财政年份: 2010
• 资助国家: 德国
• 起止时间: 2009-12-31 至 2015-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/163601529?language=en
• 关键词: blockade; neuropilin; plexin; A2; therapeutic

Loss of sympathetic nerve fibers (SNF) is a general principle in inflammatory lesions as we demonstrated in experimental arthritis, rheumatoid arthritis, Charcot arthropathy, Crohn’s disease, experimental colitis, atopic dermatitis, and others. In parallel, we found nerve repellent factors such as semaphorin 3C and 3F in inflamed tissue, which are most probably responsible for loss of SNF. In the previous project, we intended to block effects of semaphorins to allow outgrowth of SNF using an Fc-fusion construct of the semaphorin receptor neuropilin-2 (NPN-2fc). Unexpectedly, NPN-2fc had a strong agonistic effect on SNF repulsion as determined in the neurite outgrowth assay. In addition, NPN-2fc increased severity in experimental arthritis, and soluble NPN-2 was higher in synovial fluid of rheumatoid arthritis compared to osteoarthritis patients. In this present project, we want to continue this line of research by focusing on the co-receptor of NPN-2 called plexin A2 or A3. Plexin A2/A3 is the signal transducing receptor needed to build a heterotrimeric complex of neuropilin-2 and semaphorins 3F or 3C. It is the main goal in this project to neutralize both, NPN-2 together with plexin A2 (or A3), and to study effects of inhibition of this important receptor in vitro and in vivo. We will generate a super-construct of neuropilin-2 linked to plexin A2 (or A3) to be used in the outgrowth assay and in the animal model of collagen type II arthritis. On the basis of these findings, we will test further modifications of the blocking peptide in the outgrowth assay.

交感神经纤维（SNF）的损失是炎性病变的一般原理，如我们在实验性关节炎、类风湿性关节炎、夏科关节病、克罗恩病、实验性结肠炎、特应性皮炎等中所证明的。与此同时，我们在发炎组织中发现了神经排斥因子，如semaphorin 3C和3F，这很可能是SNF丢失的原因。在以前的项目中，我们打算使用脑信号蛋白受体神经纤毛蛋白-2（NPN-2fc）的Fc融合构建体来阻断脑信号蛋白的作用以允许SNF的生长。出乎意料的是，NPN-2fc对SNF排斥具有强烈的激动作用，如在神经突生长测定中所确定的。此外，NPN-2fc增加了实验性关节炎的严重程度，与骨关节炎患者相比，类风湿性关节炎患者滑液中的可溶性NPN-2更高。在本项目中，我们希望通过关注NPN-2的共同受体（称为丛蛋白A2或A3）来继续这一研究路线。丛蛋白A2/A3是构建神经毡蛋白-2和脑信号蛋白3F或3C的异源三聚体复合物所需的信号转导受体。该项目的主要目标是中和NPN-2与丛蛋白A2（或A3），并研究体外和体内抑制这种重要受体的效果。我们将产生连接到丛蛋白A2（或A3）的神经纤毛蛋白-2的超构建体，以用于生长测定和II型胶原关节炎的动物模型。在这些发现的基础上，我们将在生长测定中测试封闭肽的进一步修饰。