The role of Yes-associated protein kinase YAP1 in canonical and non-canonical Hippo pathway in the disintegrin metalloproteinase ADAM15-mediated anoikis resistance of synovial fibroblasts in rheumatoid arthritis

Yes相关蛋白激酶YAP1在经典和非经典Hippo通路中在解整合素金属蛋白酶ADAM15介导的类风湿性关节炎滑膜成纤维细胞失巢凋亡抵抗中的作用

• 批准号: 438801991
• 负责人: Professor Dr. Harald Burkhardt
• 金额: --
• 依托单位: Klinik 2 - Hämatologie/Onkologie, Rheumatologie und Infektiologie/HIV
• 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/438801991?language=en
• 关键词: role; Yes; associated; protein; kinase

Rheumatoid arthritis (RA) is the most frequent inflammatory rheumatic joint disease. Based on genetic predispositions aberrantly dysregulated immunological effector cascades lead to chronic inflammatory reactions, resulting in the proteolytic destruction of cartilage and bone, thus compromising the integrity of articular joints. A major cell population critical for these destructive processes are the synovial fibroblasts, which are activated in the inflamed synovial membrane and secrete matrix degrading enzymes. A hallmark of rheumatoid arthritis synovial fibroblasts (RASFs) is their pathophysiological increased apoptosis resistance. Also RASFs, freely swimming in inflamed synovial fluid, are vital after their loss of matrix contact, which usually induces apoptosis, thereby rendering them anoikis resistant. The underlying mechanism of their acquired anoikis resistance are poorly understood, albeit pathophysiological relevant due to their capability to expand and infiltrate into joint tissues within one affected joint, and moreover their potential to migrate into distant healthy cartilage via the circulatory system, as has been demonstrated by animal studies.In our previous studies, a marked upregulated expression of the disintegrin metalloproteinase ADAM15 has been demonstrated in synovial membranes of RA patients. Moreover, this increased ADAM15 expression confers anti-apoptotic effects upon ligation of the death receptor Fas/CD95. The aim of the present study is to analyze, whether the transcriptional coactivator YAP1 confers cytoprotective properties in (non)-canonical Hippo pathway dependent on ADAM15 upon anoikis induction in RASFs. Therefore, ADAM15-dependent YAP1-mediated signalling pathways elicited by anoikis induction will be characterized in RASFs. Based on the outcome, the application of specific signal transduction inhibitors to selectively inhibit YAP1 signalling, thereby blocking the increased anoikis resistance of RASFs, will be evaluated. Additionally, YAP1 upstream adhesion molecules and receptors will be identified as well as YAP1 downstream gene targets.The aim of the study is the elucidation of ADAM15-dependent molecular interactions in YAP1 signaling in the anoikis resistance of RASFs and the identification of new targets for a pharmacological inhibition of these aggressively destructive synovial cell population in RA.

类风湿关节炎（RA）是最常见的炎症性风湿性关节疾病。基于遗传倾向异常失调的免疫效应子级联反应导致慢性炎症反应，导致软骨和骨骼的蛋白水解破坏，从而损害关节关节的完整性。这些破坏性过程至关重要的主要细胞群是滑膜成纤维细胞，它们在发炎的滑膜中被激活并分泌矩阵降解酶。类风湿关节炎滑膜成纤维细胞（RASFS）的标志是它们的病理生理增强了凋亡耐药性。同样，在发炎的滑液中自由游泳的RASF在其失去基质接触后至关重要，这通常会诱导凋亡，从而使它们具有抗Anoikis的耐药性。他们获得的Anoikis耐药性的潜在机制知之甚少，尽管病理生理学相关，因为它们有能力扩展和渗透到一个受影响的关节内的关节组织，并通过循环系统迁移到远处健康的骨骼系统中，并且已经证明了它们的潜力通过动物研究。在我们先前的研究中，在RA患者的滑膜膜中已证明了脱甲蛋白金属蛋白酶ADAM15的明显上调的表达。此外，这种增加的ADAM15表达赋予了抗凋亡对死亡受体FAS/CD95的连接的影响。本研究的目的是分析，转录共激活因子YAP1是否赋予（非） - 按照河马途径的细胞保护特性，依赖于ADAM15的RASFS中的Anoikis诱导。因此，在RASF中将表征ADAM15依赖性YAP1介导的信号通路。基于结果，将评估特定信号转导抑制剂在选择性抑制YAP1信号传导中的应用，从而评估RASFS的抗Anoikis耐药性。此外，将鉴定YAP1上游粘附分子和受体以及YAP1下游基因靶标。在RA中对这些积极破坏性滑膜细胞群体的药理抑制。