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Repin1 and Resolvines - provocation and resolution of "silent and sterile" inflammation (inflammasome) in the progression of chronic liver diseases to HCC

Repin1 和 Resolvines - 在慢性肝病进展为 HCC 过程中引发和解决“沉默且无菌”的炎症（炎症小体）

基本信息

批准号：
281273087
负责人：
Dr. Kerstin Abshagen
金额：
--
依托单位：
Institut für Experimentelle Chirurgie mit Zentraler Versuchstierhaltung
依托单位国家：
德国
项目类别：
Research Grants
财政年份：
2015
资助国家：
德国
起止时间：
2014-12-31 至 2019-12-31
项目状态：
已结题

来源：
https://gepris.dfg.de/gepris/projekt/281273087?language=en
关键词：
Repin1 Resolvines provocation resolution silent

项目摘要

Metabolic effects, oxidative stress, and an imbalance of pro- and anti-inflammatory cytokines are of particular importance in the progression of fatty liver to hepatocellular carcinoma (HCC). During liver inflammation activation of the NLRP3 inflammasome plays a crucial role in the pathogenesis of chronic liver diseases. Therefore, reduction of the inflammatory state is of high significance for prevention and therapy of liver diseases. In this study we analyze (i) the correlation between lipid modulators, such as Repin1 and lipid mediators (resolvines), (ii) their regulation of the sterile inflammation in the progression of chronic liver diseases to HCC, (iii) their significance in humans, and (iv) aspects for prevention and therapy. The aim of this study is to evaluate whether hepatic deficiency of Repin1 attenuates progression of fatty liver to HCC by modulating the NLRP3-mediated inflammatory response in a clinically relevant experimental NASH-Fibrosis-HCC mouse model. In this context, functional relationships between Repin1-induced generation of metabolic alarm signals and a consecutive activation of NLRP3 as well as a perpetuation of the hepatic inflammation due to the lack of resolvines should be analyzed. We further focus on adiponectin as a common factor and regulator of both signaling pathways, resolvines, and NLRP3. Moreover, it should be evaluated whether a liver-specific siRNA-mediated deficiency of Repin1 or NLRP3 as well as a supply of anti-inflammatory mediators (n-3 fatty acid (diet), resolvines) represent therapeutic and preventive options for the treatment of chronic liver diseases.

代谢效应、氧化应激以及促炎细胞因子和抗炎细胞因子的失衡在脂肪肝向肝细胞癌（HCC）的进展中特别重要。在肝脏炎症过程中，NLRP 3炎性体的激活在慢性肝病的发病机制中起着至关重要的作用。因此，减轻炎症状态对于预防和治疗肝脏疾病具有重要意义。在这项研究中，我们分析了（i）脂质调节剂，如Repin 1和脂质介质（resolvines）之间的相关性，（ii）它们在慢性肝病向HCC进展中对无菌炎症的调节，（iii）它们在人类中的意义，以及（iv）预防和治疗方面。本研究的目的是评估Repin 1的肝缺陷是否通过在临床相关的实验NASH-纤维化-HCC小鼠模型中调节NLRP 3介导的炎症反应来减弱脂肪肝向HCC的进展。在这种情况下，应分析Repin 1诱导的代谢警报信号的产生和NLRP 3的连续激活以及由于缺乏resolvines而导致的肝脏炎症的持续存在之间的功能关系。我们进一步关注脂联素作为两种信号通路，resolvines和NLRP 3的共同因子和调节因子。此外，应评估肝脏特异性siRNA介导的Repin 1或NLRP 3缺陷以及抗炎介质（n-3脂肪酸（饮食），resolvines）的供应是否代表慢性肝病治疗的治疗和预防选择。