Role of a novel IKK-related kinase in inflammation

描述（由申请人提供）：类风湿性关节炎（RA）是一种慢性炎症性疾病，可导致对称性多关节炎和关节破坏。RA发病机制中的大量工作涉及调节促炎介质产生的多种信号通路。特别是NF-kB起着关键作用，IkB激酶-2（IKK 2）是一个有吸引力的治疗靶点。然而，这种激酶的阻断引起了主要的安全性问题。因此，我们集中在最近描述的激活先天免疫反应和NF-κ B的替代途径。IKK相关激酶，诱导型IKK（IKKi）和TANK结合激酶1（TBK 1）最初被鉴定为磷酸化IkB的NF-κ B激活激酶。然而，现在很清楚，这只是IKKi的几种底物之一。例如，IKKi磷酸化干扰素调节因子3（IRF）并在Toll样受体（TLR）连接后与NF-kB协调其活化。IKKi还可能在LPS刺激的细胞中连接NF-κ B和CCAAT增强子结合蛋白（C/EBP）途径。我们的初步数据表明，IKKi可以激活c-Jun和增强MMP在培养的滑膜细胞的表达。我们假设IKKi激活RA的先天性和适应性免疫，并代表了一种新的方法来阻断与滑膜炎症有关的致病性转录因子激活。我们建议通过首先确定IKKi在滑膜细胞中激活的信号转导途径来评估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IKKi敲除小鼠和野生型小鼠中关节炎的被动K/BxN模型以及在DBA/1背景下杂交的IKKi敲除小鼠中胶原诱导的关节炎模型来确定IKKi在动物模型中的作用。这些实验将允许评估IKKi作为RA治疗靶点的潜力。风湿性关节炎（RA）在许多患者中导致关节破坏和严重残疾，影响全球高达1%的成年人口。研究RA中激活的细胞内通路可能会导致预防和开发这种慢性衰弱性疾病的新疗法。

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.