Co-stimulatory interactions in the development of Non-Alcoholic Steatohepatitis and Liver Fibrosis

非酒精性脂肪性肝炎和肝纤维化发展中的共刺激相互作用

• 批准号: 396067872
• 负责人: Dr. Antonios Chatzigeorgiou
• 金额: --
• 依托单位: Laboratory of Experimental Physiology
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2018
• 资助国家: 德国
• 起止时间: 2017-12-31 至 2021-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/396067872?language=en
• 关键词: Co; stimulatory; interactions; development; Non

Obesity is strongly associated with pathologies such as insulin resistance and non-alcoholic fatty liver disease (NAFLD). The low grade inflammatory state present in obesity is a major component of the progression of NAFLD to non-alcoholic steatohepatitis (NASH), a disorder characterised by exacerbated hepatocellular injury that can lead to fibrosis, cirrhosis or even neoplasia. Although the study of inflammatory mechanisms implicated in the promotion of hepatic lipid accumulation, liver damage and fibrosis is a major target of NASH research, very little is known about the cellular interactions amongst cells of the innate and adaptive immunity as well as between immune cells and parenchymal cells of the liver that lead to NASH development. Therefore, in the current proposal, the applicant aims to unravel the pathophysiological events that determine the interactions between parenchymal cells, innate immunity and adaptive immunity in the steatotic liver environment, by focusing on a major player of cell-to-cell communication processes, the CD40/CD40L system. Our in vivo and in vitro preliminary data suggest that the CD40/CD40L duo has a predominant role in the hepatic immune-parenchymal cell crosstalk and thereby in the regulation of hepatic steatosis and progression to NASH. To this end, we will utilize genetically modified mice, including mice with hepatocyte- and myeloid/macrophage cell-specific ablation of CD40, as well as mice with lymphocyte-specific deletion of CD40L that will be assessed for diet-induced development of NAFLD and NASH. In addition, we will thoroughly investigate the molecular events (intercellular or intracellular) that are responsible for the CD40/CD40L-dependent regulation of steatohepatitis. We expect that these findings will significantly improve our understanding of the inflammatory cell interplay in the liver during NASH development and may pave the way for novel therapeutic strategies to prevent obesity-related NAFLD and transition to NASH.

肥胖与胰岛素抵抗和非酒精性脂肪肝（NAFLD）等病理密切相关。肥胖中存在的低度炎症状态是NAFLD进展为非酒精性脂肪性肝炎（NASH）的主要组成部分，NASH是一种以肝细胞损伤加剧为特征的疾病，可导致纤维化、肝硬化甚至肿瘤形成。尽管与促进肝脂质积累、肝损伤和纤维化有关的炎症机制的研究是NASH研究的主要目标，但对导致NASH发展的先天性和适应性免疫细胞之间以及免疫细胞和肝实质细胞之间的细胞相互作用知之甚少。因此，在本提案中，申请人旨在通过关注细胞间通讯过程的主要参与者CD 40/CD 40 L系统，来阐明决定脂肪变性肝脏环境中实质细胞、先天免疫和适应性免疫之间相互作用的病理生理学事件。我们的体内和体外初步数据表明，CD 40/CD 40 L二人组在肝脏免疫实质细胞串扰中具有主导作用，从而在肝脏脂肪变性和NASH进展的调节中具有主导作用。为此，我们将利用遗传修饰小鼠，包括具有肝细胞和骨髓/巨噬细胞特异性CD 40消融的小鼠，以及具有淋巴细胞特异性CD 40 L缺失的小鼠，这些小鼠将评估饮食诱导的NAFLD和NASH发展。此外，我们将彻底研究负责脂肪性肝炎的CD 40/CD 40 L依赖性调节的分子事件（细胞间或细胞内）。我们预计，这些发现将显著提高我们对NASH发展过程中肝脏中炎症细胞相互作用的理解，并可能为预防肥胖相关NAFLD和向NASH过渡的新治疗策略铺平道路。