Role of TLR7 in progression and treatment of alcoholic hepatitis

项目摘要 酒精性肝病(ALD)是长期摄入过量酒精的结果。在美国，40%的 与肝脏相关的死亡与饮酒有关。ALD的范围从酒精性脂肪 肝、酒精性肝炎(AH)、酒精性肝硬变和肝细胞癌(肝细胞癌)。虽然酒精性脂肪 肝脏被认为是一种良性肝病，急性肝炎的死亡率很高，因为40%的重症急性肝炎患者在 六个月。AH的治疗仍在很大程度上依赖于皮质类固醇和己酮可可碱，没有显著意义 在过去的40年里取得了进步。由于观察到肠源性内毒素(LPS)的移位 在ALD中，Toll样受体(TLR)信号转导参与了ALD的发生发展。为. 十年以来，我们研究了TLR介导的ALD的分子机制，并探讨了其治疗作用 以TLR为目标的特工。TLR2、TLR4和TLR9信号通路促进ALD的发生发展。我们以前的 研究发现，TLR7信号在肝纤维化中的保护作用，这与其他TLR相反 促进肝病。到目前为止，TLR7信号和TLR7信号转导通路保护作用的分子机制 肝病中TLR7的天然配体知之甚少。此外，TLR7的功能作用 AH中的信号是未知的。这一建议的中心假设是TLR7信号是负面的 肝脏炎症的调节剂，可以防止AH的恶化，并激活TLR7信号可能是 一种治疗急性肝炎的有效方法。在这项拟议的研究中，目标1将描述 TLR7介导的急性肝炎肝保护作用。目标2将寻找TLR7的内源性配体并研究其作用 外切体作为TLR7内源配体的载体。Aim 3将研究一种新的TLR7配体，它高度 作为一种潜在的治疗手段，TLR7比现有的TLR7配体更安全。如果拟议的研究是 我们的结果将为TLR7信号的新机制提供重要的见解 以及TLR7在AH中的内源性配体，以及治疗AH的新途径。

Project Summary Alcoholic liver disease (ALD) is a result of chronic intake of excessive alcohol. In the United States, 40% of liver-related death is associated with alcohol consumption. The spectrum of ALD ranges from alcoholic fatty liver, alcoholic hepatitis (AH), alcoholic cirrhosis and hepatocellular carcinoma (HCC). Although alcoholic fatty liver is considered a benign liver disease, the mortality of AH is high, as 40 % of severe AH patients die within 6 months. Treatment of AH is still largely dependent on corticosteroid and pentoxifylline, with no significant progress in the past 40 years. Since the translocation of intestine-derived lipopolysaccharide (LPS) is observed in ALD, it is conceivable that Toll-like receptor (TLR) signaling contributes to the development of ALD. For a decade, we have investigated the molecular mechanisms of TLR-mediated ALD and examined the therapeutic agents targeting TLRs. TLR2, TLR4, and TLR9 signaling promotes the development of ALD. Our previous study found the protective role of TLR7 signaling in liver fibrosis, which is in contrast to other TLRs that promote liver disease. To date, the molecular mechanisms of the protective effect of TLR7 signaling and natural ligands for TLR7 in liver disease are poorly understood. In addition, the functional role of TLR7 signaling in AH is unknown. The central hypothesis of this proposal is that TLR7 signaling is a negative regulator of liver inflammation, which prevents exacerbation of AH, and activation of TLR7 signaling could be an effective therapy for AH. In the proposed study, Aim 1 will characterize the molecular mechanisms of the TLR7-mediated liver protection in AH. Aim 2 will seek the endogenous ligands for TLR7 and examine the role of exosomes as vehicles for TLR7 endogenous ligands. Aim 3 will examine a novel TLR7 ligand that is highly safer than existing TLR7 ligands as a potential therapeutic approach for AH. If the proposed study is successfully achieved, our results will provide significant insights into the new mechanisms of TLR7 signaling and endogenous ligands for TLR7 in AH, and the new therapeutic approach for AH.