RvD1-FPR2 signaling ameliorates alcoholic liver disease

RvD1-FPR2信号传导可改善酒精性肝病

基本信息

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
项目类别：
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

项目摘要

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) 是一种预后不良的病态，主要由酒精性肝炎的改变引起免疫细胞对内毒素血症作出反应，但其机制尚不完全清楚或明白了。 Resolvin D1 (RvD1) 是一种促解析脂质介质，通过甲酰基发出信号小鼠肽受体 2 (FPR2) 引起巨噬细胞 M2 极化并抗菌在中性粒细胞中发挥作用。 AH 中血浆 RvD1 水平和肝脏 FPR2 表达降低患者表明该通路在 AH 中受到阻碍。动物模型建议 RvD1 治疗改善 Fpr2-/- 小鼠酒精引起的肝损伤、炎症、纤维化和内毒素血症加重肝损伤、炎症、纤维化和内毒素血症。研究表征酒精性肝病 (ALD) 中不存在 RvD1-FPR2 信号通路，但根据初步数据进行保证。目标 1：该目标将决定 RvD1 是否仅通过 FPR2 可对动物的酒精性肝病 (ALD) 产生保护作用。目标 2：目标 2a 将决定如果 RvD1-FPR2 信号通路对于 Kupffer 细胞的 M2 极化至关重要。目标 2b 将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。目标 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 RvD1 离体处理，然后进行流式细胞术和蛋白质组学分析磷酸蛋白质组学分析可测量受体激活并表征信号传导路径，分别。总的来说，这项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的严重性以及AH的分析患者对这项研究进行了采样，它对未来的治疗立即产生影响并提供信息策略。新型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信号通路的基础生物学这项工作也预计会产生中性粒细胞和单核细胞。