TWEAK-Fn14 regulation of non-canonical NF-kB signaling in chronic renal inflammation

摘要 据估计，美国有3700万人患有慢性肾病(CKD)，即 肾小管萎缩的以由于结构性炎症、纤维化和肾小管萎缩而导致的肾功能稳步下降为特征的 目前的治疗方法只能减缓CKD的进展。因此，新的治疗方法 CKD是迫切需要的。核因子-- 与炎症有关。然而，虽然规范的NF- 复合证据表明，非正则核因子- 响应 Kb转录因子家族是一个众所周知的信号通路，它是 KB信号已经得到了深入的研究，有 KB信号在支持持续性炎症中起关键作用 。肿瘤坏死因子相关的弱凋亡诱导因子及其受体成纤维细胞 生长因子诱导的14(Fn14，也称为TNFRSF12a)是为数不多的已发现的非 典型的核因子-- KB信令。 研究表明，TWEW诱导的非典范神经营养因子- KB信令已提升 在肾脏疾病模型中，并激活促炎细胞因子和趋化因子以响应急性和 肾脏持续受损。尽管近年来在理解上取得了重大进展 非正则的核因子- KB信令，我们对下行信令的了解仍然存在很大差距 机制切换到不同的路径以响应TTHINE刺激，但对其如何变化知之甚少 TWILE与更知名的细胞因子如肿瘤坏死因子协同作用 这一提议的假设是TWAKE诱导的非正则核因子- 与肿瘤坏死因子相比，独特的炎症信号 要：1)确定TWAINE如何激活非规范的核因子- 通过规范的核因子- 肾细胞中α和IL-6的表达。中环 肾细胞中的KB信号刺激 α驱动的典型的核因子-kB信号。这项提议旨在 肾细胞中的KB Kb激活剂；2)确定relA和p52转录因子活性的不同特征，以及 以及这些反应是如何被调制的 顺铂处理的Fn14基因敲除小鼠的免疫反应；以及3)设计并验证一种细胞测试，该细胞测试报告 无论是正则的还是非正则的- 用于高通量筛选(HTS)的实时Kb信令 Fn14修饰剂和抑制剂。这项提案的预期结果是，我们将定义关键组件 区分正则和非正则的核因子- Kb信号，我们将开发一种新的筛选方法 这将是一个有用的工具，有助于我们进一步了解肾脏细胞的慢性炎症。而其他的研究 关注肿瘤坏死因子 α和更多成熟的细胞因子，这一建议解决了我们知识中的一个重大差距 论核因子与核因子之间的相互作用 KB信号通路，更具体地说，非规范的NF- KB信令 协同作用调节炎症。

ABSTRACT An estimated 37 million people in the United States suffer from chronic kidney disease (CKD), which is characterized by steadily declining kidney function due to constitutive inflammation, fibrosis, and tubular atrophy. Current therapeutic approaches are only able to slow CKD progression. Thus, new therapeutic approaches for CKD are urgently required. The NF- associated with inflammation. However, while canonical NF- compounding evidence that non-canonical NF- response kB family of transcription factors is a well-known signaling pathway that is kB signaling has been intensely studied, there is kB signaling plays a key role in supporting sustained inflammatory . Tumor necrosis factor (TNF)-related weak inducer of apoptosis (TWEAK) and its receptor fibroblast growth factor-inducible 14 (Fn14, also named TNFRSF12a) are among the few identified regulators of non- canonical NF- kB signaling. Studies have shown that TWEAK-induced non-canonical NF- kB signaling is elevated in models of kidney disease and activates proinflammatory cytokines and chemokines in response to acute and sustained kidney injury. Despite the significant progress that has been made in recent years in understanding non-canonical NF- kB signaling, there remains a significant gap in our knowledge of how downstream signaling mechanisms switch to divergent pathways in response to TWEAK stimulation, and less is known about how TWEAK works in synergy with more well-known cytokines such as TNF hypothesis of this proposal is that TWEAK-induced non-canonical NF- unique inflammatory signature when compared to TNF to: 1) Identify how TWEAK activates non-canonical NF- by canonical NF- α and IL-6 in renal cells. The central kB signaling in renal cells stimulates a α-driven canonical NF- kB signaling. This proposal seeks kB in renal cells kB activators; 2) Determine distinct signatures of RelA and p52 transcription factor activity and and how these responses are modulated immune response in cisplatin treated Fn14 knockout mice; and 3) Engineer and validate a cell assay that reports both canonical and non-canonical NF- kB signaling in real time for high-throughput screening (HTS) of TWEAK- FN14 modifiers and inhibitors. The anticipated outcome of this proposal is that we will define key components that differentiate canonical from non-canonical NF- kB signaling, and we will develop a novel screening assay that will be a useful tool in furthering our understanding of chronic inflammation in renal cells. While other studies focus on TNF α and more well-established cytokines, this proposal addresses a significant gap in our knowledge on the interplay between NF- kB signaling pathways and more specifically, how non-canonical NF- kB signaling works in concert to modulate inflammation.