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）是一种预后不良的疾病，主要是由改变的 免疫细胞对内毒素血症的反应，但其机制尚不完全清楚， 明白Resolvin D1（RvD 1）是一种促消退脂质介质，通过甲酰基 小鼠中的肽受体2（FPR 2）引发巨噬细胞中的M2极化和抗菌 在中性粒细胞中起作用。AH患者血浆RvD 1水平和肝脏FPR 2表达降低 患者表明该途径在AH中受阻。动物模型表明RvD 1治疗 改善酒精诱导的肝损伤、炎症、纤维化和内毒素血症，而Fpr 2-/-小鼠 出现肝损伤、炎症、纤维化和内毒素血症加剧。表征的研究 酒精性肝病（ALD）中RvD 1-FPR 2信号通路不存在，但 根据初步数据。目标1：该目标将确定RvD 1是否仅通过以下方式起作用： FPR 2在酒精性肝病（ALD）动物中引发保护作用。目标2：目标2a将决定 RvD 1-FPR 2信号通路是否对枯否细胞的M2极化至关重要。目标2b将 确定RvD 1-FPR 2信号传导是否是嗜中性粒细胞介导的防御反应所必需的， 病原体威胁目的3：AH患者和健康对照获得中性粒细胞和单核细胞 将用或不用RvD 1离体处理，然后进行流式细胞术和蛋白质组学， 磷酸蛋白质组学分析，以测量受体活化并表征信号传导 路，分别。总体而言，本研究将生成可识别RvD 1或FPR 2的数据 激动剂作为ALD的治疗方法。由于AH的严重性和AH的分析 患者样本本研究立即产生影响，并为未来的治疗提供信息 战略布局新的生物标志物和治疗干预措施预计将来自 建议研究的结论。RvD 1-FPR 2信号通路的基础生物学 嗜中性粒细胞和单核细胞也可从这项工作中得到。