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

非酒精性脂肪性肝病（NAFLD）全球患病率为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）及相关纤维化是NAFLD的进行性形式，目前尚无药物治疗方法。尽管NAFLD进展的机制尚不完全清楚，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。慢性炎症改变肝脏的生理耐受性，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）和纤维化导致NASH中起关键作用。CD44（细胞表面糖蛋白）信号是由ECM分子（骨桥蛋白（OPN）、透明质酸（HA）和间接张力蛋白c (TNC)）启动的，可以增强信号强度和持续时间。OPN、HA、TNC和CD44可以与细胞表面受体（如c-Met、VEGFR、TLR4、EGFR、CXCR4....）形成复合物，已知这些受体促进炎症、血管生成和纤维生成。我们提出CD44作为中心整合器和增强器，通过将ECM的信号传递到细胞质中，从而触发驱动NAFLD的促炎信号。事实上，该联盟已经发现，靶向CD44通过下调巨噬细胞和中性粒细胞进入肝脏的募集，并通过降低OPN水平和TNC信号传导，强烈缓解肝损伤、脂肪性肝炎和纤维化。在患者中，肝脏CD44和TNC表达相互密切相关，并与肝巨噬细胞浸润/丰度密切相关，表明这两种分子在NAFLD中共同起作用。MATRIXNASH的目标是：1。通过蛋白质组学和基因组学方法，在具有工程水平的关键候选药物（如CD44， OPN， TNC）的小鼠NAFLD模型中，破译促进NAFLD发生和进展的ecm依赖途径。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AAV递送系统，单独或联合靶向候选（CD44， TNC），通过一般或肝细胞类型特异性方法。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来自小鼠模型（1006名肥胖患者队列）的候选组织分析，全面了解人类NAFLD中ECM和CD44复合物的组成。与人类疾病相关的候选药物将在细胞培养和小鼠NAFLD模型中得到证实。该联盟将采用一种通用的多学科方法，结合无偏蛋白质组学、转基因小鼠模型、CD44和TNC的新型治疗靶点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。

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.