The role BH3 and multi BH domain genes in regulating monocyte survival and functi

BH3和多BH结构域基因在调节单核细胞存活和功能中的作用

• 批准号: 7774805
• 负责人: Harris R Perlman
• 金额: $ 18.33万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-08-01 至 2010-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7774805
• 关键词: Affect; Animals; Ankle; Apoptosis; Apoptotic; Arthritis; Autoimmune Diseases; BH3 Domain; BH3 peptide; Bone and Cartilage Funding; Cell Death; Cells; Cessation of life; Chemicals; Collaborations; Data; Development; Disease; Disease remission; Dominant-Negative Mutation; Edema; Embryo; Equilibrium; Family; Family member; Genes; Goals; Growth; Human body; Hyperplasia; Immune; Inflammation; Inflammatory; Inflammatory Response; Interleukin-1; Interleukin-6; Intra-Articular Injections; Joints; K/BxN model; Lead; Macrophage Activation; Measures; Mediating; Modeling; Molecular; Mus; Numbers; Pathway interactions; Patients; Peptides; Phase; Production; Proteins; Regulation; Rheumatoid Arthritis; Role; Severities; Signal Transduction; Stimulus; TNF gene; TNFRSF5 gene; Therapeutic; Tissues; base; cell growth; cell type; chemokine; cytokine; inhibitor/antagonist; macrophage; member; monocyte; mouse model; mutant; novel therapeutics; outcome forecast; pro-apoptotic protein; response; tumor

DESCRIPTION (provided by applicant): Rheumatoid arthritis (RA) is an autoimmune disease characterized by hyperplasia of the synovial lining, inflammation, and destruction of cartilage and bone. In RA, the balance between anti- and pro-apoptotic members of the Bcl-2 family may be shifted towards survival. We demonstrated that the anti-apoptotic proteins, Bcl-2 and Mcl-1 are increased while the pro-apoptotic protein Bim is decreased in RA synovial tissue as compared to controls. The study of deficiencies in anti-apoptotic members of the Bcl-2 family is complicated by embryonic lethality or early post-natal death. In contrast, mice deficient in pro-apoptotic Bcl-2 members such as Bak, Bax, or Bim survive and reach adulthood. Since Bim is a critical activator of apoptosis through sequestering Bcl-2/Mcl-1 and/or by activating Bak and Bax and since Bim is decreased in RA synovial tissue, Bim is a potential target for treatment of RA. We demonstrated that mice lacking the apoptotic initiator Bim but not the downstream effectors Bak or Bax develop a more severe form of inflammatory arthritis. This exacerbated disease in Bim-/- mice is associated with decreased apoptosis, increased expression of pro-inflammatory molecules, and more macrophages in pannus. Further, Bim-/- macrophages display elevated levels of IL-6, IL-1¿, and TNFa and enhanced expression of CD40 and CD69 in response to stimulation with LPS. Based on these data, we hypothesize that the ratio of Bim to Bcl-2 and/or Mcl- 1 serves as molecular rheostat that determines the extent of hyperplasia and activation of macrophages in the joint. We will use a pharmacological approach, a whole animal approach, and a cell-specific approach to identify how deficiency in Bim exacerbates inflammatory arthritis. These studies will potentially lead to novel therapeutic approaches to RA. The regulation of cell death and growth is vital for maintaining a balance in the human body. However, during the initiation and/or progression of the autoimmune disease, rheumatoid arthritis (RA), the balance is disrupted. In RA there is an increase in cellular growth and a concomitant decrease in cell death leading to an abnormal increase in the tissue that attaches to the cartilage/bone junction, the synovial lining. Analysis of tissue from joints of patients with RA revealed that the number of macrophages correlated with a worse prognosis. Monocytes (macrophage precursors) and macrophages are immune cells that produce the noxious factors in patients with RA and are responsible for removing dying cells or debris in tissues. We demonstrated that the death signaling cascade mediated by the pro-death protein Bim is dysfunctional in macrophages from patients with RA. Additionally, we have shown that mice lacking Bim in all cell types develop a worse form of arthritis and that the macrophages from these mice are highly activated, meaning they produce significant amounts of deleterious factors that exacerbate the inflammation. Therefore, our goal is to develop a therapeutic to activate the Bim death pathway and inhibit or induce remission in RA. Further our goal is to characterize mice lacking Bim or it signaling partners only in monocytes and macrophages.

描述（由申请人提供）：类风湿性关节炎（RA）是一种自身免疫性疾病，其特征是滑膜内膜增生、炎症以及软骨和骨的破坏。在RA中，Bcl-2家族的抗凋亡和促凋亡成员之间的平衡可能转向生存。我们发现，与对照组相比，RA滑膜组织中的抗凋亡蛋白Bcl-2和Mcl-1增加，而促凋亡蛋白Bim减少。Bcl-2家族抗凋亡成员的缺陷研究因胚胎致死或早期产后死亡而复杂化。相比之下，缺乏促凋亡Bcl-2成员如Bak、Bax或Bim的小鼠存活并进入成年期。由于Bim通过隔离Bcl-2/Mcl-1和/或激活Bak和Bax是细胞凋亡的关键激活因子，并且由于Bim在RA滑膜组织中减少，因此Bim是治疗RA的潜在靶点。我们证明缺乏凋亡引发物Bim而不缺乏下游效应物Bak或Bax的小鼠会发展成更严重的炎症性关节炎。在Bim-/-小鼠中，这种加重的疾病与细胞凋亡减少、促炎分子表达增加和pannus中巨噬细胞增多有关。此外，在LPS刺激下，Bim-/-巨噬细胞显示出IL-6、IL-1¿和TNFa水平升高，CD40和CD69表达增强。基于这些数据，我们假设Bim与Bcl-2和/或Mcl- 1的比例是决定关节内巨噬细胞增生和活化程度的分子变阻器。我们将使用药理学方法、全动物方法和细胞特异性方法来确定Bim缺乏如何加剧炎症性关节炎。这些研究将有可能为类风湿关节炎带来新的治疗方法。细胞死亡和生长的调节对维持人体的平衡至关重要。然而，在自身免疫性疾病，类风湿性关节炎（RA）的开始和/或进展过程中，这种平衡被破坏。在类风湿性关节炎中，细胞生长增加，同时细胞死亡减少，导致附着于软骨/骨连接处（滑膜衬里）的组织异常增加。对RA患者关节组织的分析显示，巨噬细胞的数量与较差的预后相关。单核细胞（巨噬细胞前体）和巨噬细胞是类风湿性关节炎患者产生有害因子的免疫细胞，负责清除组织中垂死的细胞或碎片。我们证明由死亡前蛋白Bim介导的死亡信号级联在RA患者巨噬细胞中功能失调。此外，我们已经证明，所有细胞类型中缺乏Bim的小鼠患关节炎的情况更严重，这些小鼠的巨噬细胞高度活化，这意味着它们会产生大量有害因子，从而加剧炎症。因此，我们的目标是开发一种治疗方法来激活Bim死亡途径，抑制或诱导RA的缓解。进一步，我们的目标是表征仅在单核细胞和巨噬细胞中缺乏Bim或it信号伴侣的小鼠。