Role of TLR7 in progression and treatment of alcoholic hepatitis

TLR7在酒精性肝炎进展和治疗中的作用

• 批准号: 10190743
• 负责人: EKIHIRO SEKI
• 金额: $ 42.3万
• 依托单位: CEDARS-SINAI MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-01 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10190743
• 关键词: Adrenal Cortex Hormones; Agonist; Alcohol abuse; Alcohol consumption; Alcoholic Fatty Liver; Alcoholic Hepatitis; Alcoholic Liver Cirrhosis; Alcoholic Liver Diseases; Alcoholic beverage heavy drinker; Animal Model; Anti-Inflammatory Agents; Antiinflammatory Effect; Attenuated; Benign; Blood; Blood Circulation; Cells; Cessation of life; Cholestasis; Chronic; Clinical; Clinical Trials; Data; Development; Disease; Equilibrium; Ethanol; Fibrosis; Future; Goals; Heavy Drinking; Hepatitis C; Hepatocyte; Human; Imiquimod; Inflammation; Inflammatory; Interferon-alpha; Intestines; Kupffer Cells; Ligands; Lipopolysaccharides; Liver; Liver Fibrosis; Liver diseases; Mediating; MicroRNAs; Modeling; Molecular; Mus; Pathway interactions; Patients; Pentoxifylline; Play; Primary carcinoma of the liver cells; Production; Property; RNA; Receptor Signaling; Recombinants; Reporting; Role; Signal Transduction; Source; Specimen; TLR2 gene; TLR4 gene; TLR7 gene; Testing; Therapeutic; Therapeutic Agents; Therapeutic Effect; Toll-like receptors; Toxin; Translating; United States; Virus; animal data; circulating microRNA; cost effective treatment; effective therapy; exosome; improved; insight; interleukin-22; liver inflammation; mortality; nonalcoholic steatohepatitis; novel; novel therapeutic intervention; preclinical study; prevent; protective effect; small molecule; targeted treatment; therapeutic evaluation

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.

项目摘要 酒精性肝病（ALD）是慢性摄入饮酒的结果。在美国，有40％ 与肝有关的死亡与饮酒有关。 ALD范围从酒精脂肪范围 肝脏，酒精性肝炎（AH），酒精性肝硬化和肝细胞癌（HCC）。虽然酒精脂肪 肝脏被认为是良性肝病，AH的死亡率很高，因为40％的严重AH患者死亡 6个月。 AH的治疗仍然很大程度上取决于皮质类固醇和五氧化氨酸，没有明显的 过去40年的进展。由于观察到肠道来源的脂多糖（LPS）的易位 在ALD中，可以想象，Toll样受体（TLR）信号传导有助于ALD的发展。对于 十年，我们研究了TLR介导的ALD的分子机制，并检查了治疗性 针对TLR的代理。 TLR2，TLR4和TLR9信号传导促进了ALD的发展。我们的先前 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。迄今为止，TLR7信号传导的保护作用的分子机制和 肝病中TLR7的天然配体知之甚少。另外，TLR7的功能作用 AH中的信号未知。该提案的中心假设是TLR7信号是一个负 防止AH加重的肝脏炎症调节剂，TLR7信号的激活可能是 AH的有效疗法。在拟议的研究中，AIM 1将表征分子机制 TLR7介导的AH肝脏保护。 AIM 2将为TLR7寻求内源配体并检查角色 外泌体作为TLR7内源配体的车辆。 AIM 3将检查一种新颖的TLR7配体 比现有的TLR7配体更安全，作为AH的潜在治疗方法。如果拟议的研究是 成功实现了，我们的结果将为TLR7信号的新机制提供重大见解 AH中TLR7的内源配体以及AH的新治疗方法。