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， 肝脏相关的死亡与饮酒有关。ALD的光谱范围从酒精脂肪 肝、酒精性肝炎（AH）、酒精性肝硬化和肝细胞癌（HCC）。虽然酒精脂肪 肝脏被认为是一种良性肝病，AH的死亡率很高，因为40%的重度AH患者在 6个月AH的治疗仍然在很大程度上依赖于皮质类固醇和戊茶碱， 过去40年的进步。由于观察到精氨酸衍生的脂多糖（LPS）的移位， 在ALD中，可以想象Toll样受体（TLR）信号传导有助于ALD的发展。用于 十年来，我们研究了TLR介导的ALD的分子机制，并检查了治疗方法。 靶向TLR的药物。TLR2、TLR4和TLR9信号转导促进ALD的发展。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， 促进肝脏疾病。到目前为止，TLR7信号转导保护作用的分子机制和 对肝病中TLR7的天然配体知之甚少。此外，TLR7的功能作用 AH中的信令是未知的。该提议的中心假设是TLR7信号传导是负性的。 肝脏炎症调节因子，防止AH恶化，TLR7信号转导的激活可能是 AH的有效治疗方法。在拟议的研究中，目标1将表征 TLR7介导的AH中的肝脏保护。目的2寻找TLR7的内源性配体，并研究其在调节TLR7表达中的作用。 外泌体作为TLR7内源性配体的载体。目的3将研究一种新的TLR7配体， 比现有的TLR7配体更安全，作为AH的潜在治疗方法。如果拟议的研究 成功实现，我们的结果将提供重要的见解TLR7信号转导的新机制 以及AH中TLR7的内源性配体，以及AH的新治疗方法。

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.