Role of a novel IKK-related kinase in inflammation

描述(申请人提供)：类风湿性关节炎(RA)是一种慢性炎症性疾病，导致对称性多发性关节炎和关节破坏。在类风湿关节炎的发病机制中，已有大量的工作涉及调节促炎介质产生的多条信号通路。尤其是核因子-kB起着关键作用，而IKB激酶-2(IKK2)是一个很有吸引力的治疗靶点。然而，阻断这种激酶会引起重大的安全问题。因此，我们将重点放在最近描述的激活先天性免疫反应和核因子-kB的另一条途径上。IKK相关的激酶，诱导型IKK(IKK)和TANK-BINDING KEK1(TBK1)最初被认为是使IKB磷酸化的核因子-kB激活的激酶。然而，现在很明显，这只代表了Ikki的几个底物之一。例如，Ikki使干扰素调节因子3(IRF)磷酸化，并在Toll样受体(TLR)连接后将其激活与NF-kB协调。在脂多糖刺激的细胞中，Ikki也可能起到连接NF-kB和CCAAT增强子结合蛋白(C/EBP)途径的作用。我们的初步数据表明，Ikki可以激活c-jun，增强培养的滑膜细胞中基质金属蛋白酶的表达。我们假设Ikki同时激活了RA的先天免疫和获得性免疫，并代表了一种新的方法来阻断与滑膜炎症有关的致病转录因子的激活。我们建议通过首先确定Ikki在滑膜细胞中激活的信号转导通路来评估Ikki在滑膜炎症中的作用。然后，我们将确定Ikki在RA患者滑膜组织和滑膜细胞中的功能和调节。最后，我们将通过研究在Ikki基因敲除和野生型小鼠中被动的K/BxN关节炎模型以及在DBA/1背景下杂交的Ikki基因敲除小鼠的胶原蛋白诱导的关节炎模型来确定Ikki在动物模型中的作用。这些实验将评估Ikki作为类风湿关节炎治疗靶点的潜力。类风湿性关节炎(RA)在许多患者中导致关节破坏和严重残疾，影响到全球高达1%的成年人。对RA中激活的细胞内通路的研究可能会导致这种慢性、衰弱疾病的预防和新疗法的开发。

DESCRIPTION (provided by applicant): Rheumatoid arthritis (RA) is a chronic inflammatory disease that causes symmetric polyarthritis and joint destruction. Considerable work in the pathogenesis of RA has implicated multiple signaling pathways that regulate the production of pro-inflammatory mediators. NF-kB, in particular, plays a key role, and IkB kinase- 2 (IKK2) is an attractive therapeutic target. However, blockade of this kinase poses major safety concerns. As a result, we have focused on a recently described alternate pathway that activates innate immune responses and NF-kB. The IKK-related kinases, inducible IKK (IKKi) and TANK-binding kinase 1 (TBK1) were as originally identified as NF-kB activating kinases that phosphorylated IkB. It is now clear, however, that this represents only one of several substrates for IKKi. For instance, IKKi phosphorylates interferon regulatory factor 3 (IRF) and coordinates its activation with NF-kB after Toll-like receptor (TLR) ligation. IKKi might also serve to link the NF-kB and CCAAT enhancer binding protein (C/EBP) pathways in LPS stimulated cells. Our preliminary data indicate that IKKi can activate c-Jun and enhance MMP expression in cultured synoviocytes. We hypothesize that IKKi activates both innate and adaptive immunity in RA and represents a novel approach to blocking pathogenic transcription factor activation implicated in synovial inflammation. We propose to assess the role of IKKi in synovial inflammation by first determining the signal transduction pathways activated by IKKi in synoviocytes. We will then determine the function and regulation of IKKi in synovial tissue and synoviocytes from RA patients. Finally, we will determine the role of IKKi in animal models by studying a passive K/BxN model of arthritis in IKKi knockout and wild type mice as well as a collagen-induced arthritis model in IKKi knockout mice crossbred on the DBA/1 background. These experiments will allow an assessment of the potential of IKKi as a therapeutic target in RA. Rheumatoid arthritis (RA) causes joint destruction and significant disability in many patients, affecting up to 1% of the adult population worldwide. Studies of the intracellular pathways activated in RA might lead to prevention and development of novel therapies for this chronic, debilitating disease.