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: 10442533
• 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 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10442533
• 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.

项目概要 酒精性肝病（ALD）是长期摄入过量酒精的结果。在美国，40% 肝脏相关死亡与饮酒有关。 ALD 的范围从酒精性脂肪 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 肝脏被认为是一种良性肝脏疾病，AH的死亡率很高，40%的严重AH患者会在短时间内死亡。 6个月。 AH 的治疗在很大程度上仍依赖于皮质类固醇和己酮可可碱，但效果并不显着。 过去40年的进步。由于观察到肠源性脂多糖 (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。对于一个 十年来，我们研究了 TLR 介导的 ALD 的分子机制，并检验了治疗方法 针对 TLR 的药物。 TLR2、TLR4 和 TLR9 信号传导促进 ALD 的发展。我们之前的 研究发现 TLR7 信号传导在肝纤维化中具有保护作用，这与其他 TLR 信号相反 促进肝脏疾病。迄今为止，TLR7信号传导保护作用的分子机制和 对于肝脏疾病中 TLR7 的天然配体知之甚少。此外，TLR7的功能作用 AH 中的信号传导未知。该提案的中心假设是 TLR7 信号传导是负向的 肝脏炎症的调节因子，可防止 AH 恶化，TLR7 信号传导的激活可能是 AH 的有效治疗方法。在拟议的研究中，目标 1 将描述其分子机制 AH 中 TLR7 介导的肝脏保护作用。目标 2 将寻找 TLR7 的内源配体并检查其作用 外泌体作为 TLR7 内源配体的载体。目标 3 将检查一种新型 TLR7 配体，该配体高度 作为 AH 的潜在治疗方法，比现有的 TLR7 配体更安全。如果拟议的研究是 成功实现，我们的结果将为 TLR7 信号传导的新机制提供重要的见解 AH 中 TLR7 的内源性配体，以及 AH 的新治疗方法。

项目成果

Hepatocyte TGF-β Signaling Inhibiting WAT Browning to Promote NAFLD and Obesity Is Associated With Let-7b-5p.

• DOI: 10.1002/hep4.1892
• 发表时间: 2022-06
• 期刊: Hepatology communications
• 影响因子: 5.1

Alcoholic liver disease: A current molecular and clinical perspective.

• DOI: 10.1016/j.livres.2018.11.002
• 发表时间: 2018-12-01
• 期刊: Liver research
• 作者: Ohashi, Koichiro;Pimienta, Michael;Seki, Ekihiro
• 通讯作者: Seki, Ekihiro

Serum Glial Cell Line-Derived Neurotrophic Factor (sGDNF) Is a Novel Biomarker in Predicting Cirrhosis in Patients with Chronic Hepatitis B.

• DOI: 10.1155/2022/1048104
• 发表时间: 2022
• 期刊: CANADIAN JOURNAL OF GASTROENTEROLOGY AND HEPATOLOGY
• 影响因子: 2.7
• 作者: Yang, Guangyue;Zhuang, Liping;Sun, Tiantian;Yeo, Yee Hui;Tao, Le;Zhang, Wei;Ma, Wenting;Wu, Liu;Yang, Zongguo;Yang, Yanqin;Xue, Dongying;Zhang, Jie;Feng, Rilu;Matthias, Ebert P.;Dooley, Steven;Seki, Ekihiro;Liu, Ping;Liu, Cheng
• 通讯作者: Liu, Cheng