Impact of the aberrant cell-matrix interaction in Non-Alcoholic fatty liver diseases progression

异常细胞-基质相互作用对非酒精性脂肪肝疾病进展的影响

• 批准号: 431336276
• 负责人: Professor Dr. Dirk Grimm
• 金额: --
• 依托单位: Abteilung Virologie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2019
• 资助国家: 德国
• 起止时间: 2018-12-31 至 2022-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/431336276?language=en
• 关键词: Impact; aberrant; cell; matrix; interaction

Non-Alcoholic fatty liver diseases (NAFLD) with a 25% worldwide prevalence are leading causes of liver associated morbidity and mortality. No pharmacological treatment is yet available for chronic inflammation/Non-Alcoholic SteatoHepatitis (NASH) and associated fibrosis that are the progressive forms of NAFLD. Although the mechanisms underlying NAFLD progression are not fully understood, chronic inflammation is a key player mediating dysfunction of liver, adipose tissue and the gut. Chronic inflammation modifies the physiological tolerance of the liver and promotes liver injury and fibrogenesis. The extracellular matrix (ECM) and its receptors play a key role in orchestrating chronic inflammation (liver, adipose tissue) and fibrosis leading to NASH. Signaling by CD44 (cell-surface glycoprotein) is initiated by ECM molecules (osteopontin (OPN), hyaluronan (HA), and indirectly tenascin-C (TNC)) that may enhance signal intensity and duration. OPN, HA, TNC and CD44 can form complexes with cell surface receptors (e.g. c-Met, VEGFR, TLR4, EGFR, CXCR4….) that are known to promote inflammation, angiogenesis and fibrogenesis. We propose that CD44 acts as a central integrator and potentiator by transmitting signals from the ECM into the cytoplasm thus triggering proinflammatory signaling that drives NAFLD. Indeed, the consortium already discovered that targeting CD44 strongly alleviates liver injury, steatohepatits and fibrosis by downregulating the recruitment of macrophages and neutrophils into the liver and, by decreasing OPN levels and TNC signaling. In patients, hepatic CD44 and TNC expression strongly correlates with each other and with hepatic macrophage infiltration/abundance suggesting a combined action of both molecules in NAFLD. The aims of MATRIXNASH are: 1.-To decipher the ECM-dependent pathways promoting onset and progression of NAFLD by proteomic and genomic approaches in murine NAFLD models with engineered levels of key candidates (e.g. CD44, OPN, TNC). 2.-To establish novel therapeutic strategies in our fibrotic-NASH models by targeting candidates (CD44, TNC) alone or in combination through general or hepatic cell type specific approaches using novel state of the art AAV delivery systems. 3.-To establish relevance for the human patient in an integrative approach. We will gain comprehensive knowledge about ECM and CD44 complex composition in human NAFLD by proteomic and genomic approaches and tissue analysis for candidates derived from the murine models (cohort of 1006 obese patients). Candidates, relevant in the human disease, will be confirmed in cell culture and our murine NAFLD models. The consortium will employ a common multidisciplinary approach combining unbiased proteomics, transgenic mouse models, novel therapeutic targeting of CD44 and TNC and a large cohort of human tissue samples to acquire comprehensive knowledge about NAFLD onset and progression. This information may provide novel tools for diagnosis and therapy of NAFLD.

非酒精性脂肪性肝病（NAFLD）在全球范围内的患病率为25%，是肝脏相关发病率和死亡率的主要原因。慢性炎症/非酒精性脂肪性肝炎（NASH）和相关纤维化是NAFLD的进行性形式，目前尚无药物治疗。虽然NAFLD进展的机制尚未完全了解，但慢性炎症是介导肝脏，脂肪组织和肠道功能障碍的关键因素。慢性炎症改变了肝脏的生理耐受性，并促进肝损伤和纤维化。细胞外基质（ECM）及其受体在协调慢性炎症（肝脏、脂肪组织）和导致NASH的纤维化中发挥关键作用。通过CD 44（细胞表面糖蛋白）的信号传导由ECM分子（骨桥蛋白（OPN）、透明质酸（HA）和间接地生腱蛋白-C（TNC））启动，其可增强信号强度和持续时间。OPN、HA、TNC和CD 44可以与细胞表面受体（例如c-Met、VEGFR、TLR 4、EGFR、CXCR 4.它们能促进炎症血管生成和纤维化。 我们认为CD 44通过将信号从ECM传递到细胞质中，从而触发驱动NAFLD的促炎信号传导，作为中心整合剂和增强剂。事实上，该联盟已经发现，靶向CD 44通过下调巨噬细胞和中性粒细胞向肝脏的募集以及通过降低OPN水平和TNC信号传导来强烈减轻肝损伤，脂肪肝和纤维化。在患者中，肝脏CD 44和TNC表达彼此强烈相关，并且与肝脏巨噬细胞浸润/丰度强烈相关，表明两种分子在NAFLD中的联合作用。MATRIXNASH的目标是：1.通过蛋白质组学和基因组学方法，在具有工程化水平的关键候选物（例如，CD 44、OPN、TNC）的小鼠NAFLD模型中解读促进NAFLD发作和进展的ECM依赖性途径。2.-在我们的纤维化NASH模型中建立新的治疗策略，通过使用最先进的新型AAV递送系统，通过一般或肝细胞类型特异性方法单独或组合靶向候选物（CD 44，TNC）。3.-以综合方法建立与人类患者的相关性。我们将通过蛋白质组学和基因组学方法以及对来自小鼠模型（1006名肥胖患者的队列）的候选人的组织分析，获得关于人类NAFLD中ECM和CD 44复合物组成的全面知识。与人类疾病相关的候选物将在细胞培养物和我们的鼠NAFLD模型中确认。该联盟将采用一种通用的多学科方法，结合无偏见的蛋白质组学、转基因小鼠模型、CD 44和TNC的新型治疗靶向以及大量人体组织样本，以获得有关NAFLD发病和进展的全面知识。这些信息可能为NAFLD的诊断和治疗提供新的工具。