Importance of the tyrosine phosphatase receptor type zeta (PTPRZ) and its ligands (Interleukin-34, Pleitrophin, Tenascin and Midkine) in the pathogenesis of lupus nephritis and systematic manifestations

zeta 型酪氨酸磷酸酶受体 (PTPRZ) 及其配体（白介素 34、Pleitropin、Tenascin 和 Midkine）在狼疮性肾炎发病机制和系统表现中的重要性

• 批准号: 261683854
• 负责人: Professorin Dr. Julia Weinmann-Menke
• 金额: --
• 依托单位: Schwerpunkt für Nephrologie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/261683854?language=en
• 关键词: Importance; tyrosine; phosphatase; receptor; type

Systemic lupus erythematosus (SLE) is an autoimmune systemic disease of unclear etiology that can affect almost any organ system. Kidney involvement (lupus nephritis) is crucial for patient morbidity and mortality. The infiltration of the kidney by T-cells and macrophages (Mø) (mononuclear cells) is, in addition to the deposition of immunoglobulins, glomerular and interstitial, an important histomorphological characteristic of lupus nephritis and also has an important prognostic significance. The necessary immunosuppressive therapy of SLE is not unproblematic due to its undesirable effects and complications in the mostly young female patients (disease peak 20-40 years of age, ratio of female to male patients 10:1). The identification of factors (cytokines, interferons) responsible for the initiation and progression of lupus nephritis and SLE could therefore lead to promising new, more specific therapy approaches or options for therapy monitoring. Using a lupus mouse model, we could demonstrate the pathogenesis-promoting role of Colony Stimulating Factor-1 (CSF-1), which is expressed by renal tubule epithelial cells and binds to the CSF-1 receptor. However, IL-34 also binds to CSF-1R as a second ligand. In recent studies we could show that IL-34 alone plays a relevant role in the pathogenesis of lupus nephritis and systemic manifestation and that IL-34 deficiency is not compensated by the CSF-1 CSF-1R signaling pathway. A hypothesis of the cause of these results could be that IL-34 is involved in the pathogenesis of lupus nephritis via its second receptor, the tyrosine phosphatase receptor type Z (PTPRZ). In addition, the PTPRZ receptor has further ligands that have already been associated with inflammatory processes and fibrosis formation: the extracellular matrix protein tenascin C (Tnc) and the heparin-binding growth factors pleiotrophin (Ptn) and midkine (Mdk). In this project we will therefore investigate the role of the receptor PTPRZ and its ligands (PTN, MdK, Tnc and IL-34) in the pathogenesis of acute and chronic renal damage in lupus nephritis and systemic manifestations in SLE. The significance of the knowledge gained primarily in the mouse model on the role of the function of PTPRZ and its ligands will be investigated translationally in human SLE in order to broaden the understanding of the pathogenesis of human SLE, especially in the presence of renal and musculoskeletal manifestations. In summary, the knowledge gained will then be used to develop new therapeutic targets-options as well as new diagnostic markers for lupus nephritis and systemic manifestations.

系统性红斑狼疮（SLE）是一种病因不明的自身免疫性系统性疾病，几乎可以影响任何器官系统。肾脏受累（狼疮性肾炎）对患者的发病率和死亡率至关重要。除了免疫球蛋白、肾小球和间质的沉积之外，T细胞和巨噬细胞（MRF）（单核细胞）对肾脏的浸润是狼疮肾炎的重要组织形态学特征，并且也具有重要的预后意义。SLE的必要的免疫抑制治疗并非没有问题，因为其在大多数年轻女性患者中的不良反应和并发症（疾病高峰年龄为20-40岁，女性与男性患者的比例为10：1）。因此，识别负责狼疮肾炎和SLE的启动和进展的因素（细胞因子，干扰素）可能会导致有前途的新的，更具体的治疗方法或治疗监测的选择。使用狼疮小鼠模型，我们可以证明集落刺激因子-1（CSF-1）的发病促进作用，CSF-1由肾小管上皮细胞表达并与CSF-1受体结合。然而，IL-34也结合CSF-1 R作为第二配体。在最近的研究中，我们可以表明，IL-34单独在狼疮性肾炎和系统性表现的发病机制中起着相关的作用，并且IL-34缺乏不能通过CSF-1 CSF-1 R信号通路来补偿。这些结果的原因的假设可能是IL-34通过其第二受体，酪氨酸磷酸酶受体Z型（PTPRZ）参与狼疮性肾炎的发病机制。 此外，PTPRZ受体还具有与炎症过程和纤维化形成相关的其他配体：细胞外基质蛋白生腱蛋白C（Tnc）和肝素结合生长因子多效生长因子（Ptn）和中期因子（Mdk）。因此，在本项目中，我们将研究受体PTPRZ及其配体（PTN，MdK，Tnc和IL-34）在狼疮肾炎和系统性红斑狼疮的急性和慢性肾损害的发病机制中的作用。主要在小鼠模型中获得的关于PTPRZ及其配体功能作用的知识的意义将在人类SLE中进行初步研究，以扩大对人类SLE发病机制的理解，特别是在存在肾脏和肌肉骨骼表现的情况下。总之，所获得的知识将用于开发新的治疗靶点选择以及狼疮性肾炎和全身表现的新诊断标志物。