The role of Mcl-1 in the macrophages and RA

单核细胞/巨噬细胞对宿主免疫反应至关重要，并参与了霍乱的发病机制。 类风湿关节炎(RA)。我们证明了依赖于PI3K/Akt-L的Mcl-1的表达在 巨噬细胞存活。抑制PI3K/Akt降低Mcl-1的表达，导致细胞凋亡 通过线粒体途径。也通过反义寡核苷酸强制下调Mcl-1 诱导细胞凋亡，表明Mcl-1是巨噬细胞存活所必需的。另外，我们初步的 研究表明，Mcl-1在人巨噬细胞中也可能受JAK/STAT信号通路的调控。 因此，我们建议确定PI3K/Akt和JAK/STAT3通路的机制 有助于调节巨噬细胞中Mcl-1的表达。此外，我们将确定通过哪些机制 MCL-1通过检测McL-1与促凋亡分子的相互作用来保护巨噬细胞，如 Bax在巨噬细胞中的表达，以阐明Mcl-1引起的线粒体功能障碍的机制 消融。我们的初步数据表明，Mcl-1可能在维持RA的生存中起重要作用 滑膜巨噬细胞。此外，我们的初步数据显示，在体外，Mcl-1高度 在RA中表达，与骨关节炎(OA)、滑膜成纤维细胞相比。MCL-1在卵巢癌中也有较强表达。 佐剂性关节炎(AIA)大鼠的滑膜。因此，我们建议将 Mcl-1在RA关节中的表达和功能，检测巨噬细胞和滑膜成纤维细胞。我们 建议确定强制下调Mcl-1是否会改善实验性关节炎， 这表明Mcl-1在关节炎的发生和/或发展中起着重要作用。因此，这项提议 将描述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和巨噬细胞之间潜在的细胞类型特异性差异。 正常，骨关节炎和类风湿性关节炎滑膜成纤维细胞。这些实验将提供新的和 关于McL-1的新角色的重要信息，这些信息可能提供将导致 类风湿性关节炎患者改进治疗的发展。 Performmanceite(S)(组织、市、州) 西北大学医学院 风湿科内科 芝加哥大道东303号 3-315病区 芝加哥，IL 60611 关键人员。请参阅说明。根据需要使用辅助页面toprovidetherequiredinformationintheformatshownbelow. 从首席调查员开始，其他关键人员按字母顺序排列，姓氏在前。 名称组织角色项目 理查德·M·波普，西北大学医学博士 刘洪涛，西北大学医学博士，共同研究员 哈里斯·珀尔曼，西北大学博士，共同研究员 G.Kenneth Haines，MD西北大学联合调查员 披露许可声明。适用于SBIR/STRONNY。请参阅说明。[]是[_否 ？PHS 398(05/01版)第2页表单第2页。 ？首席调查项目主任(最后、第一、中间)：Pope，Richard，M 必须在每张打印页和每张续页的顶部提供首席调查员/项目主任的姓名。 研究补助金 目录 页码 Face Page........................................................................................................................1 描述，

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(S) (organization,city, state) Northwestern University Medical School Department of Medicine, Division of Rheumatology 303 E Chicago Ave Ward 3-315 Chicago, IL 60611 KEY PERSONNEL. See instructions.Usecontinuation pages as needed toprovidetherequiredinformationintheformatshownbelow. StartwithPrincipalInvestigatorL¿ istallotherkeypersonnelinalphabeticaol rder,lastnamefirst. Name Organization Roleon Project Richard M. Pope, MD Northwestern University PI Hongtao Liu, MD PhD Northwestern University Co-investigator Harris Perlman, PhD Northwestern University Co-investigator G. Kenneth Haines, MD Northwestern University Co-investigator Disclosure Permission Statement. Applicableto SBIR/STTROnly. See instructions.[] Yes [_ No ¿ PHS 398 (Rev. 05/01) Page2 Form Page 2. ¿ Principal InvestigatodProgram Director (Last, first, middle): Pope, Richard, M The name of the principal investigator/program director must be provided at the top of each printed page and each continuation page. RESEARCH GRANT TABLE OF CONTENTS Page Numbers Face Page.................................................................................................................................................. 1 Description,