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

TWEAK-Fn14 对慢性肾脏炎症中非经典 NF-kB 信号传导的调节

• 批准号: 10742538
• 负责人: Michael A. Ortega
• 金额: $ 66.75万
• 依托单位: QUEEN'S MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-15 至 2026-08-14
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10742538
• 关键词: Acute; Address; Affect; Apoptosis Promoter; Atrophic; Attenuated; Autoimmune Diseases; Biological Assay; CRISPR/Cas technology; Cell Death; Cell Line; Cell model; Cells; Cellular Assay; Chronic; Chronic Kidney Failure; Cisplatin; Clinical Trials; Collaborations; Data; Dendritic Cells; Disease; Disease Progression; Dose; Engineering; Environment; Epithelium; Exposure to; Failure; Family; Fibroblast Growth Factor Receptors; Fibroblasts; Fibrosis; Functional disorder; Gene Expression Profile; Genetic; Genetic Transcription; Goals; Hawaii; I-kappa B Proteins; Immune; Immune response; Individual; Induction of Apoptosis; Infiltration; Inflammation; Inflammatory; Inflammatory Response; Injury; Injury to Kidney; Interleukin-6; KB Cells; Kidney; Kidney Diseases; Knock-out; Knockout Mice; Knowledge; Libraries; Lupus Nephritis; Lymphocyte; Macrophage; Measures; Mediating; Medical center; Modeling; Mus; NF-kappa B; NFKB Signaling Pathway; Names; Natural Products; Outcome; Pathway interactions; Patients; Persons; Physiological; Play; Production; Recurrence; Regulation; Renal function; Reporting; Research; Screening procedure; Signal Pathway; Signal Transduction; TNF gene; Technology; Testing; Therapeutic; Time; Tissues; Tubular formation; United States; Validation; Variant; Work; chemokine; combinatorial; cytokine; drug discovery; high throughput screening; immunoregulation; inflammatory milieu; inhibitor; interest; kidney cell; member; mouse model; nephrotoxicity; novel; novel therapeutic intervention; pressure; recruit; response; screening; synergism; therapeutic target; tool; transcription factor; transcriptome sequencing

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.

抽象的 美国估计有3700万人患有慢性肾脏病（CKD）， 特征是由于组成型感染，纤维化和管状萎缩而逐渐下降。 当前的治疗方法只能减慢CKD的进展。那是新的治疗方法 迫切需要CKD。 NF- 与炎症有关。但是，同时nf- 非经典nf-的复合证据 回复 KB转录因子家族是一种众所周知的信号通路 KB信号已积极研究，有 KB信号在支持持续炎症方面起着关键作用 。肿瘤坏死因子（TNF）相关的细胞凋亡（TWEAK）及其受体成纤维细胞 生长因子诱导14（FN14，也称为TNFRSF12A）是少数已确定的非 - 规范nf- KB信号。 研究表明，调整诱导的非典型的NF- KB信号升高 在肾脏疾病模型中，激活促炎细胞因子和趋化因子，以响应急性和 持续的肾脏受伤。尽管近年来在理解方面取得了重大进展 非典型的nf- KB信号传导，我们对下游信号传导的了解存在很大的差距 机制响应调整刺激而切换到发散的途径，而对如何进行了了解 调整与更知名的细胞因子（例如TNF）的协同作用 该提议的假设是调整的非典型的NF- 与TNF相比，独特的炎症签名 到：1）确定如何激活非规范的NF- 通过规范的nf- 肾细胞中的α和IL-6。中央 肾细胞中的KB信号传导刺激A α驱动的规范NF-KB信号传导。该建议寻求 肾细胞中的KB KB激活剂； 2）确定RELA和p52转录因子活性和 以及如何调制这些响应 顺铂治疗的FN14基因敲除小鼠的免疫反应； 3）工程和验证报告的细胞测定法 规范和非典型的NF- 实时的KB信令进行调整的高通量筛查（HTS） - FN14修饰符和抑制剂。该提案的预期结果是我们将定义关键组成部分 与非典型的NF-区分了规范 KB信号传导，我们将开发一种新颖的筛选测定 这将是进一步了解肾细胞中慢性感染的有用工具。而其他研究 专注于TNF α和更完善的细胞因子，该提案在我们所知中解决了一个很大的差距 在NF-之间的相互作用上 KB信号通路，更具体地说，如何非典型的NF- KB信号 协同工作以调节炎症。