Immune Modulation of Macrophages in Obstructive Cholestasis

巨噬细胞在阻塞性胆汁淤积中的免疫调节

• 批准号: 10040905
• 负责人: Sarah Ann Taylor
• 金额: $ 24.42万
• 依托单位: LURIE CHILDREN'S HOSPITAL OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-06-01 至 2022-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10040905
• 关键词: Adult; Agonist; Anti-Inflammatory Agents; Bile Acids; Bile fluid; Biliary; Biliary Atresia; Biological Markers; Bone Marrow; C57BL/6 Mouse; Cells; Characteristics; Child; Childhood; Cholestasis; Clinical; Clinical Research; Computational Biology; Data; Data Discovery; Data Set; Disease; Disease Progression; Ensure; Etiology; Evaluation; Foundations; Future; Genetic Transcription; Hepatic; Heterogeneity; Hour; Human; Immune; Immune response; Immune system; Immunology; Immunomodulators; Immunotherapy; Inflammation; Inflammatory; Inflammatory Response; Injury; Knowledge; Laboratories; Laboratory Markers; Leukocytes; Ligation; Liver; Liver diseases; Medical; Modeling; Mus; Myeloid Cells; Obstruction; Operative Surgical Procedures; Orphan; PTPRC gene; Pathogenesis; Patients; Physiology; Play; Population; Primary biliary cirrhosis; RORA gene; Recovery; Research; Retinoic Acid Receptor; Role; Sampling; Sampling Studies; System; Therapeutic; Therapeutic Trials; Tissues; Translating; Transplantation; United States; analog; bile acid metabolism; bile duct; cholestatic injury; cholestatic liver disease; disease phenotype; experimental study; human disease; immunomodulatory therapies; immunoregulation; innovation; liver injury; liver transplantation; macrophage; mouse model; new therapeutic target; non-alcoholic; nonalcoholic steatohepatitis; novel; outcome forecast; patient population; predicting response; prevent; primary sclerosing cholangitis; receptor; repaired; response; restoration; retinoic acid receptor alpha; single-cell RNA sequencing; tissue injury; treatment strategy

PROJECT SUMMARY: Obstructive cholestatic liver diseases carry a high medical burden as there is no medical therapy to prevent disease progression and thus they remain a leading indication for liver transplantation. While the initial target in obstructive cholangiopathies is the bile duct, the immune response is the major cause for ongoing liver injury. Macrophages are known to play a significant role in the mechanism of cholestatic liver injury, however, disease- modulating immunotherapies have not been established and represent an unmet medical need. We have been the first to perform single-cell RNA sequencing (scRNA-seq) on cholestatic liver samples and will use this preliminary data in the current study to overcome the gap in medical therapy. We have identified a subset of RORA-expressing macrophages in cholestatic liver samples that is at the interface between cholestatic and normal macrophages on pseudotime trajectory analysis. RORA encodes a retinoic acid receptor-related orphan receptor alpha (ROR) that is known to promote anti-inflammatory polarization of human macrophages. Our data suggests that RORA+ macrophages may emerge in cholestatic liver injury and thus be a novel therapeutic target. While ROR-agonism has shown improvement in hepatic injury in a murine model of non-alcoholic steatohepatitis, the role of RORA in cholestatic liver disease has not been investigated. We hypothesize that RORA+ hepatic macrophages are necessary for the reparative response after cholestatic injury; thus, ROR agonism will promote repair through the conversion of pro-inflammatory macrophages into this critical pro-restorative subset. We will investigate our hypothesis through: 1) correlation between clinical parameters of liver injury and the transcriptional prolife of RORA+ hepatic macrophages in cholestatic and non-cholestatic human liver diseases using scRNA-seq, 2) identification of the reparative macrophage immune response after alleviation of biliary obstruction using an innovative murine model of reversible bile duct ligation, and 3) evaluation of changes in disease phenotype in our murine model upon ROR-agonism. Transcriptional correlation between human and murine macrophage subsets will provide the foundation to translate findings from the current study into future human immune-modulatory therapeutic trials. In addition, data obtained from this proposal will enable further studies on ROR-agonism in disease-specific murine models of cholestasis as well as fate-mapping experiments to determine the origin (bone-marrow derived versus tissue-resident) of the ROR-responsive macrophages.

项目摘要： 阻塞性胆汁淤积性肝脏疾病伴有高医疗灼伤，因为没有医疗疗法可以防止 疾病进展，因此它们仍然是肝移植的主要指标。而最初的目标 阻塞性胆管病是胆管，免疫反应是持续肝损伤的主要原因。 众所周知，巨噬细胞在胆固性肝损伤机理中起重要作用，但是，疾病 - 调节免疫疗法尚未建立，代表未满足的医疗需求。我们去过 第一个在胆固醇肝样品上执行单细胞RNA测序（SCRNA-SEQ），并将使用此 当前研究中的初步数据克服了医疗疗法的差距。 我们已经确定了胆固性肝样品中表达Rora的巨噬细胞的子集 在假局段轨迹分析中胆固性巨噬细胞和正常巨噬细胞之间。 Rora编码视黄酸 受体相关的孤儿受体α（ROR）已知可以促进人类的抗炎极化 巨噬细胞。我们的数据表明，Rora+巨噬细胞可能会出现在胆固性肝损伤中，因此是 一个新型的热目标。鼠模型中的ror-agyism在肝炎损伤方面有所改善 在非酒精性脂肪性肝炎中，尚未研究RORA在胆固醇肝病中的作用。我们 假设RORA+肝巨噬细胞对于频率响应是必需的 胆固性损伤；因此，Ror激动剂将通过促炎性转化来促进修复 巨噬细胞进入这个关键的促成子集。 我们将通过以下方式研究我们的假设：1）肝损伤临床参数与 Rora+肝巨噬细胞的转录促进性胆汁淤积和非色菌巨噬细胞 使用scrna-seq，2）鉴定减轻胆道后的修复性巨噬细胞免疫反应 使用可逆胆管连接的创新鼠模型的阻塞，3）评估 疾病表型在我们的鼠模型模型中。人与人之间的转录相关性 鼠巨噬细胞子集将为将当前研究的发现转化为未来的基础 人类免疫调节治疗试验。此外，从本提案获得的数据将进一步 研究促进疾病特异性鼠模型以及脂肪映射实验的研究 确定ROR反应性巨噬细胞的起源（骨髓派生与组织居民​​）。