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.

类风湿性关节炎（RA）是最常见的炎症性风湿性关节疾病。基于遗传易感性，异常失调的免疫效应级联可导致慢性炎症反应，导致软骨和骨的蛋白水解破坏，从而损害关节的完整性。对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基质降解酶。类风湿性关节炎滑膜成纤维细胞（RASFs）的一个特征是其病理生理上增加的细胞凋亡抵抗。此外，rasf在炎症滑液中自由游动，在失去基质接触后至关重要，这通常会诱导细胞凋亡，从而使它们具有抗风湿性。它们获得性耐药的潜在机制尚不清楚，尽管病理生理相关，因为它们能够在一个受影响的关节内扩张和浸润到关节组织中，而且它们有可能通过循环系统迁移到远处的健康软骨中，动物研究已经证明了这一点。在我们之前的研究中，已经证实在RA患者的滑膜中，崩解素金属蛋白酶ADAM15的表达明显上调。此外，ADAM15表达的增加在连接死亡受体Fas/CD95时具有抗凋亡作用。本研究的目的是分析转录共激活因子YAP1是否在依赖ADAM15的（非）规范Hippo通路中通过anoikis诱导rasf具有细胞保护特性。因此，由anoikis诱导引发的adam15依赖性yap1介导的信号通路将在rasf中表征。基于该结果，我们将评估特异性信号转导抑制剂选择性抑制YAP1信号传导从而阻断rasf增加的anoikis抗性的应用。此外，YAP1上游粘附分子和受体以及YAP1下游基因靶点也将被确定。本研究的目的是阐明在类风湿性关节炎（RA）中，YAP1信号通路中adam15依赖的分子相互作用，并确定药物抑制这些具有侵略性破坏性的滑膜细胞群的新靶点。