RvD1-FPR2 signaling ameliorates alcoholic liver disease

RvD1-FPR2信号传导可改善酒精性肝病

• 批准号: 10160633
• 负责人: Josiah E Hardesty
• 金额: $ 6.64万
• 依托单位: UNIVERSITY OF LOUISVILLE
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-05-01 至 2022-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10160633
• 关键词: Aftercare; Agonist; Alcohol consumption; Alcoholic Hepatitis; Alcoholic Liver Diseases; Alcoholic steatohepatitis; Alcohols; Animal Model; Animals; Anti-Bacterial Agents; Bacteria; Biology; Cell Extracts; Cell physiology; Cells; Cessation of life; Chronic; Cirrhosis; Data; Disease model; Dopamine D1 Receptor; Endotoxemia; Ethanol; Exposure to; FPR2 gene; Fatty Liver; Fibrosis; Flow Cytometry; Future; Genes; Hepatic; Histologic; Human; Immune; Immune response; Immunology; Infection; Inflammation; Inflammatory Response; Kupffer Cells; Label; Lead; Ligands; Liver; Liver diseases; Measures; Mediating; Modeling; Morbidity - disease rate; Mus; Pathogenesis; Pathogenicity; Pathology; Pathway interactions; Patients; Phagocytes; Phagocytosis; Plasma; Play; Population; Prognosis; Proteomics; Receptor Activation; Receptor Cell; Regimen; Resolution; Respiratory Burst; Role; Sampling; Sampling Studies; Serum; Severities; Signal Pathway; Signal Transduction; Stimulus; Therapeutic; Tissues; Work; alcohol exposure; antimicrobial; base; chronic liver disease; cytokine; defense response; feeding; healthy volunteer; lipid mediator; liver inflammation; liver injury; macrophage; monocyte; mortality; neutrophil; novel marker; novel therapeutic intervention; phosphoproteomics; prevent; response; standard care; treatment strategy

Alcoholic hepatitis (AH) is a morbid condition with poor prognosis that is primarily driven by altered immune cell function in response to endotoxemia, but the mechanisms are not fully known or understood. Resolvin D1 (RvD1) is a pro-resolution lipid mediator that signals through formyl peptide receptor 2 (FPR2) in mice eliciting M2 polarization in macrophages and antibacterial functions in neutrophils. Plasma RvD1 levels and hepatic FPR2 expression are decreased in AH patients suggesting this pathway is impeded in AH. Animal models suggest RvD1 treatment ameliorates alcohol induced liver injury, inflammation, fibrosis, and endotoxemia while Fpr2-/- mice develop exacerbated liver injury, inflammation, fibrosis, and endotoxemia. Studies characterizing the RvD1-FPR2 signaling pathway in alcoholic liver disease (ALD) are nonexistent but are warranted based on preliminary data. Aim 1: This aim will determine if RvD1 acts solely through FPR2 to elicit protection in an animal of alcoholic liver disease (ALD). Aim 2: Aim 2a will determine if the RvD1-FPR2 signaling pathway is essential for M2 polarization of Kupffer cells. Aim 2b will establish if RvD1-FPR2 signaling is required for neutrophil-mediated defense responses against pathogenic threats. Aim 3: AH patient and healthy control acquired neutrophils and monocytes will be treated with or without RvD1 ex vivo followed by flow cytometry and proteomic and phosphoproteomic analysis to measure receptor activation and to characterize the signaling pathway, respectively. Collectively this study will generate data that could identify RvD1 or FPR2 agonists as a therapeutic approach for ALD. Due to the severity of AH and the analysis of AH patient samples this study it is immediately impactful and informative for future treatment strategies. Novel biomarkers and therapeutic interventions are expected to come from the conclusion of the proposed study. Basic biology of the RvD1-FPR2 signaling pathway in neutrophils and monocytes is expected from this work as well.

酒精性肝炎（AH）是病态疾病，预后不良，主要由改变驱动 免疫细胞功能响应内毒素血症，但这些机制尚不完全知道或 理解。 Resolvin D1（RVD1）是一种促分辨率的脂质介质，该脂质介质通过甲酰基发出信号 在巨噬细胞和抗菌中引起M2极化的小鼠中的肽受体2（FPR2） 中性粒细胞的功能。在AH中，血浆RVD1水平和肝FPR2表达降低 提示此途径的患者在AH中受到阻碍。动物模型建议RVD1治疗 改善酒精诱导的肝损伤，炎症，纤维化和内毒素血症，而FPR2 - / - 小鼠 发展恶化的肝损伤，炎症，纤维化和内毒素血症。特征的研究 酒精性肝病（ALD）中的RVD1-FPR2信号传导途径不存在，但 根据初步数据进行保证。目标1：此目标将确定RVD1是否仅通过 FPR2在酒精性肝病动物（ALD）中引起保护。 AIM 2：AIM 2A将确定 如果RVD1-FPR2信号通路对于Kupffer细胞的M2极化至关重要。 AIM 2B会 确定中性粒细胞介导的防御反应是否需要RVD1-FPR2信号传导 致病威胁。 AIM 3：AH患者和健康控制获得了中性粒细胞和单核细胞 将接受或不带RVD1的离体处理，然后进行流式细胞仪和蛋白质组学，以及 磷酸蛋白质组学分析以测量受体激活并表征信号传导 途径分别。总的来说，本研究将生成可以识别RVD1或FPR2的数据 激动剂作为ALD的治疗方法。由于AH的严重程度和AH分析 患者样本这项研究立即影响到未来治疗的信息 策略。新颖的生物标志物和治疗干预措施预计将来自 拟议研究的结论。 RVD1-FPR2信号通路的基本生物学 从这项工作也可以期望中性粒细胞和单核细胞。