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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要：阻塞性胆汁淤积性肝病带来沉重的医疗负担，因为没有药物治疗可以预防疾病进展，因此它们仍然是肝移植的主要适应症，同时也是肝移植的最初目标。阻塞性胆管病是胆管的免疫反应，是造成肝脏持续损伤的主要原因。众所周知，巨噬细胞在胆汁淤积性肝损伤的机制中发挥着重要作用，然而，疾病- 调节免疫疗法尚未建立，并且代表了未满足的医疗需求。第一个对胆汁淤积性肝脏样本进行单细胞 RNA 测序 (scRNA-seq) 并将使用该技术目前的研究初步数据弥补了药物治疗方面的差距。我们在胆汁淤积性肝脏样本中鉴定出了表达 RORA 的巨噬细胞子集，该巨噬细胞位于界面处拟时间轨迹分析中胆汁淤积型巨噬细胞和正常巨噬细胞之间的关系 RORA 编码视黄酸。受体相关的孤儿受体α (RORα)，已知可促进人类抗炎极化我们的数据表明 RORA+ 巨噬细胞可能出现在胆汁淤积性肝损伤中。一个新的治疗靶点，而 RORα 激动剂已在小鼠模型中显示出改善肝损伤的作用。对于非酒精性脂肪性肝炎，RORA 在胆汁淤积性肝病中的作用尚未得到研究。 RORA+肝巨噬细胞对于术后修复反应是必需的胆汁淤积损伤；因此，RORα激动剂将通过促炎细胞的转化来促进修复。巨噬细胞进入这个关键的促恢复亚群。我们将通过以下方式研究我们的假设：1）肝损伤的临床参数与肝损伤的临床参数之间的相关性。 RORA+肝巨噬细胞在胆汁淤积性和非胆汁淤积性人类肝脏疾病中的转录增殖使用 scRNA-seq，2) 鉴定胆汁缓解后的修复性巨噬细胞免疫反应使用可逆胆管结扎的创新小鼠模型进行梗阻，以及 3) 评估我们的小鼠模型中 RORα 激动剂的疾病表型与人类和人类之间的转录相关性有关。小鼠巨噬细胞亚群将为将当前研究结果转化为未来奠定基础此外，从该提案中获得的数据将有助于进一步开展人体免疫调节治疗试验。疾病特异性胆汁淤积小鼠模型中 RORα 激动的研究以及命运图谱实验确定 RORα 反应性巨噬细胞的起源（骨髓来源与组织驻留）。