The role of Mcl-1 in the macrophages and RA

超出所提供的空间。单核细胞/巨噬细胞对宿主免疫反应至关重要，并与类风湿关节炎（RA）的发病机制有关。我们证明PI3K/ akt -1依赖性Mcl-1表达对巨噬细胞存活至关重要。抑制PI3K/Akt可降低Mcl-1的表达，通过线粒体途径介导细胞凋亡。通过反义寡核苷酸强制下调Mcl-1也可诱导细胞凋亡，表明Mcl-1对巨噬细胞的生存至关重要。此外，我们的初步数据表明，Mcl-1也可能在人巨噬细胞中受到JAK/STAT通路的调节。因此，我们建议确定PI3K/Akt和JAK/STAT3通路参与巨噬细胞Mcl-1调控的机制。此外，我们将通过检测Mcl-1与促凋亡分子（如巨噬细胞中的Bax）的相互作用来确定Mcl-1保护巨噬细胞的机制，以描述Mcl-1消融后发生的线粒体功能障碍的机制。我们的初步数据表明Mcl-1可能在维持RA滑膜巨噬细胞的活力中起重要作用。此外，我们的初步数据显示，与骨关节炎（OA）、滑膜成纤维细胞相比，Mcl-1在体外高表达。Mcl-1也在佐剂性关节炎（AIA）大鼠滑膜中强烈表达。因此，我们建议通过检测巨噬细胞和滑膜成纤维细胞来表征Mcl-1在RA关节中的表达和功能。我们建议确定Mcl-1的强制下调是否会改善实验性关节炎，这将表明Mcl-1是关节炎发生和/或进展的一个贡献者。因此，本研究将揭示巨噬细胞中Mcl-1的表达调控机制及其新功能。研究人员建议进一步研究巨噬细胞与正常、骨关节炎和类风湿关节炎滑膜成纤维细胞之间潜在的细胞类型特异性差异。这些实验将为Mcl-1的新作用提供新的重要信息，这可能会为改善RA患者的治疗提供见解。PERFORMANCESITE ( ======================================== 节结束 ===========================================

EXCEED THE SPACE PROVIDED. Monocytes/macrophages are vital for host-immune responses and have been implicated in the pathogenesis of rheumatoid arthritis (RA). We demonstrated that PI3K/Akt-l-dependent Mcl-1 expression is vital for macrophage survival. Suppression of PI3K/Akt reduced Mcl-1 expression, resulting in apoptosis mediated through the mitochondrial pathway. Forced downregulation of Mcl-1 through antisense oligonucleotides also induced apoptosis, demonstrating that Mcl-1 is essential for macrophage viability. Further, our preliminary data suggested that Mcl-1 may also be regulated by the JAK/STAT pathway in human macrophages. Therefore, we propose to determine the mechanisms by which the PI3K/Akt and JAK/STAT3 pathways contribute to the regulation of Mcl-1 in macrophages. Additionally, we will identify the mechanism by which Mcl-1 protects macrophages by examining the interaction of Mcl-1 with pro-apoptotic molecules, such as Bax in macrophages to delineate the mechanism of mitochondrial dysfunction that occurs following Mcl-1 ablation. Our preliminary data suggests that Mcl-1 may be important in the in maintaining the viability of RA synovial macrophages. Additionally, our preliminary data has revealed that in vitro, Mcl-1 was highly expressed in RA, compared to osteoarthritis (OA), synovial fibroblasts. Mcl-1 was also strongly expressed in the synovium of rats with adjuvant-induced arthritis (AIA). Therefore, we propose to characterize the expression and function of Mcl-1 in the RA joint, examining macrophages and synovial fibroblasts. We propose to determine if the forced downregulation of Mcl-1 will ameliorate experimental arthritis, which would indicate that Mcl-1 is a contributor to the initiation and/or progression of arthritis. Thus, this proposal will delineate the mechanisms regulating the expression and the novel functions of Mcl-1 in macrophages. Further studies are proposed to delineate potential cell type-specific differences between macrophages and normal, osteoarthritis and rheumatoid arthritis synovial fibroblasts. These experiments will provide new and important information concerning the novel role of Mcl-1, which may provide insights that will lead to the development of improved therapy for patients with RA. PERFORMANCESITE( ========================================Section End===========================================