Role of NF-kB in glomerulonephritis

转录因子NF-κB的激活通过调节细胞因子和趋化因子等关键介质在炎症性疾病中发挥关键作用。在核因子-κB的多步激活过程中，中心的激酶是IKK2(或IKKβ)和IKK1(或IKKα)。因此，这些激酶很有希望成为药物抑制NF-κB激活的靶点。在炎症过程中，IKK1和IKK2是动态激活和失活的。此外，它们以细胞谱系特有的方式受到不同的调控。本项目将集中于在新月体肾炎的实验模型中分析IKK1和IKK2对NF-κB的细胞特异性和时间依赖性的激活。了解细胞系特异性白细胞和常驻肾细胞中NF-κB的差异激活机制对快速进展性肾小球肾炎患者未来的治疗策略具有重要意义。

Activation of the transcription factor NF-κB plays a pivotal role in inflammatory diseases by regulation of key mediators such as cytokines and chemokines. The central kinases in the multistep activation process of NF-κB are IKK2 (or IKKβ) and IKK1 (or IKKα). These kinases are therefore promising targets for pharmacological inhibition of NF-κB activation. IKK1 and IKK2 are dynamically activated and inactivated in the course of inflammation. Furthermore, they are differentially regulated in a cell lineage-specific manner. This project will concentrate on the analysis of cell-specific and time-dependent activation of NF-κB by IKK1 and IKK2 in an experimental model of crescentic glomerulonephritis. Understanding of the mechanisms that are relevant in differential activation of NF-κB in cell lineage specific leukocytes as well as in resident renal cells might be of great importance for future therapeutic strategies in patients with rapidly progressive glomerulonephritis.