Understanding and modulating hepatic macrophage functionality in non-alcoholic fatty liver disease

了解和调节非酒精性脂肪肝中的肝巨噬细胞功能

• 批准号: 526061246
• 负责人: Professor Dr. Frank Tacke, Ph.D.
• 金额: --
• 依托单位: Medizinische Klinik mit Schwerpunkt Hepatologie und Gastroenterologie (CCM)
• 依托单位国家: 德国
• 项目类别: Research Grants
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/526061246?language=en
• 关键词: Understanding; modulating; hepatic; macrophage; functionality

Liver macrophages are considered key in the pathogenesis of non-alcoholic fatty liver disease (NAFLD). Macrophages can sense metabolic injury to hepatocytes, orchestrate inflammatory responses and promote fibrogenesis, but are also essential during tissue repair and regeneration. Hepatic macrophages comprise ontogenetically and functionally different subsets, including tissue-resident Kupffer cells and infiltrating monocyte-derived macrophages. State-of-the-art technologies, particularly single-cell RNA sequencing, multiplex immunostaining and spatial transcriptomics will be leveraged to characterize the functional diversity of macrophages including cell-cell interactions and identify targetable ligand-receptor pairs in human NAFLD patients. Subsequent functional studies via genetic and pharmacologic inhibition (or activation) in NAFLD mouse models and co-cultures (‘liver-on-a-chip’) will determine the role of specific macrophage subsets. We anticipate that human-based systematic analyses of macrophage heterogeneity and their interactions with neighboring cells, in conjunction with functional mouse studies, will not only provide unprecedented insights into the central but functionally diverse roles of macrophages in NAFLD, but create a pipeline of novel targets for therapeutic interventions to halt NAFLD progression or stimulate its regression. To achieve this, we seek to: 1. Define macrophage subsets via their phenotypic and spatial profile in NAFLD progression and resolution (based on human liver). 2. Identify the functional consequences of macrophage subset phenotypes on hepatic dysmetabolism, inflammation and fibrosis. 3. Characterize the prospects of rationally designed and personalized treatment approaches for modulating macrophage functionality in NAFLD. Our findings will provide a comprehensive picture of how hepatic macrophage subsets contribute to altered metabolism, inflammation and fibrosis in NAFLD and opportunities for novel therapeutic strategies.

肝巨噬细胞被认为是非酒精性脂肪性肝病（NAFLD）发病机制的关键。巨噬细胞可以感知肝细胞的代谢损伤，协调炎症反应，促进纤维化，但在组织修复和再生中也是必不可少的。肝巨噬细胞包括个体遗传学和功能上不同的亚群，包括组织常驻库普弗细胞和浸润性单核细胞来源的巨噬细胞。最先进的技术，特别是单细胞RNA测序，多重免疫染色和空间转录组学将被用来表征巨噬细胞的功能多样性，包括细胞间的相互作用，并鉴定人类NAFLD患者的靶向配体-受体对。随后在NAFLD小鼠模型和共培养（“肝脏芯片”）中通过遗传和药理学抑制（或激活）进行的功能研究将确定特定巨噬细胞亚群的作用。我们预计，基于人类的巨噬细胞异质性及其与邻近细胞相互作用的系统分析，结合功能小鼠研究，不仅将为巨噬细胞在NAFLD中的核心功能多样化作用提供前所未有的见解，而且还将为治疗干预提供新的靶点，以阻止NAFLD的进展或刺激其消退。为此，我们力求：1。通过NAFLD进展和消退中的表型和空间分布来定义巨噬细胞亚群（基于人类肝脏）。2. 确定巨噬细胞亚群表型对肝脏代谢异常、炎症和纤维化的功能后果。3. 描述合理设计和个性化治疗方法调节NAFLD巨噬细胞功能的前景。我们的研究结果将提供肝巨噬细胞亚群如何促进NAFLD代谢改变、炎症和纤维化的全面图景，并为新的治疗策略提供机会。