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）， 其特征在于由于组成性炎症、纤维化和肾小管萎缩导致的肾功能稳步下降。 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。NF- 与炎症有关。然而，尽管规范NF- 复合证据表明，非典型NF- 响应 kB家族的转录因子是众所周知的信号传导途径， kB信号已经被深入研究， kB信号传导在支持持续的炎症反应中起着关键作用。 .肿瘤坏死因子相关弱凋亡诱导因子及其受体成纤维细胞 生长因子诱导型14（Fn 14，也称为TNFRSF 12 a）是为数不多的被鉴定的非- 规范NF- kB信令 研究表明，TWEAK诱导的非典型NF-κ B-κ B表达， kB信号升高 并激活促炎细胞因子和趋化因子，以响应急性和 持续的肾损伤尽管近年来在理解上取得了重大进展， 非正则NF- kB信号，我们对下游信号如何传递的知识仍然存在很大的差距。 机制切换到不同的途径，以响应TWEAK刺激，以及较少的是知道如何 TWEAK与更知名的细胞因子如TNF协同作用 该建议假设是TWEAK诱导的非典型NF-κ B， 与TNF相比， 1）确定TWEAK如何激活非规范NF-κ B 经典NF- α和IL-6在肾细胞中的表达。中央 肾细胞中的kB信号传导刺激 α-驱动的经典NF-κ B信号传导。该提案寻求 肾细胞kB 2）确定RelA和p52转录因子活性的不同特征， 以及这些反应是如何被调节的 顺铂处理的Fn 14敲除小鼠中的免疫应答;和3）工程化并验证细胞测定，其报告 规范和非规范NF- 用于TWEAK的高通量筛选（HTS）的真实的kB信号传导- FN 14调节剂和抑制剂。这一建议的预期结果是，我们将确定关键组成部分， 区分规范和非规范NF- 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细胞中的慢性炎症。而其他研究 关注TNF α和更完善的细胞因子，这一建议解决了我们的知识的一个重大差距 关于NF-κ B之间的相互作用， kB信号通路，更具体地说，如何非经典NF-κ B的信号通路， kB信令 共同调节炎症

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.