The role of Mcl-1 in the macrophages and RA

Mcl-1 在巨噬细胞和 RA 中的作用

• 批准号: 6558192
• 负责人: Richard M. Pope
• 金额: $ 27.72万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-01-01 至 2007-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6558192
• 关键词: JAK kinase; biopsy; clinical research; cytokine; fibroblasts; gene expression; human tissue; laboratory mouse; laboratory rat; macrophage; molecular pathology; phosphatidylinositol 3 kinase; protooncogene; rheumatoid arthritis; synovial membrane; transcription factor

DESCRIPTION (provided by applicant): Monocytes/macrophages are vital for host-immune responses and have been implicated in the pathogenesis of rheumatoid arthritis (RA). We demonstrated that PI3K/Akt-1-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.

描述(申请人提供)：单核/巨噬细胞对宿主免疫反应至关重要，并与类风湿性关节炎(RA)的发病机制有关。我们证明了依赖于PI3K/Akt-1的Mcl-1的表达对巨噬细胞的生存至关重要。抑制PI3K/Akt减少Mcl-1的表达，导致线粒体途径介导的细胞凋亡。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对巨噬细胞的存活是必不可少的。此外，我们的初步数据表明，Mcl-1在人巨噬细胞中也可能受到JAK/STAT通路的调控。因此，我们建议确定PI3K/Akt和JAK/STAT3通路在巨噬细胞Mcl-1调控中的作用机制。此外，我们将通过检测Mcl-1与巨噬细胞中促凋亡分子(如Bax)的相互作用来确定Mcl-1保护巨噬细胞的机制，以描绘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滑膜巨噬细胞的活性中起重要作用。此外，我们的初步数据显示，在体外，Mcl-1在RA中高表达，而在骨关节炎(OA)和滑膜成纤维细胞中表达较高。MCL-1在佐剂性关节炎(AIA)大鼠滑膜中也有较强的表达。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。我们建议确定强制下调Mcl-1是否会改善实验性关节炎，这将表明Mcl-1是关节炎的启动和/或进展的贡献者。因此，这一建议将勾勒出Mcl-1在巨噬细胞中表达的调控机制和新的功能。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。这些实验将提供有关Mcl-1新作用的新的重要信息，这些信息可能会为开发更好的RA患者治疗方法提供见解。