Immune-Metabolic Regulation of Biliary Atresia

胆道闭锁的免疫代谢调节

• 批准号: 10645435
• 负责人: Sarah Ann Taylor
• 金额: $ 11.66万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-15 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10645435
• 关键词: 2 year old; ATAC-seq; Anti-Inflammatory Agents; Apoptotic; Area; Arginine; Bile fluid; Biliary; Biliary Atresia; Biochemical Pathway; Biological Assay; Biology; Cells; Characteristics; Childhood; Cholestasis; Chromatin; Clinical; Collaborations; Critical Pathways; Data; Diagnosis; Disease; Drainage procedure; Early identification; Epigenetic Process; Foundations; Freezing; Future; Gene Expression; Gene Expression Profile; Gene Expression Regulation; Genes; Genetic Transcription; Granulocyte-Macrophage Colony-Stimulating Factor; Hepatic; Hepatocyte; Human; Immune; Immune response; Infant; Inflammatory; Liver; Macrophage; Measures; Medical; Mentors; Metabolic; Metabolism; Modification; Mus; Nature; Nitric Oxide Synthase; Obstruction; Operative Surgical Procedures; Outcome; Pathogenesis; Pathway interactions; Patient-Focused Outcomes; Patients; Phenotype; Polyamines; Predictive Value; Prognostic Marker; Putrescine; ROC Curve; Regulation; Research; Research Personnel; Rheumatology; Role; Running; Sampling; Serum; Spermidine; Spermine; Survival Rate; Time; Transplantation; Transposase; Up-Regulation; Validation; cell dedifferentiation; cohort; differential expression; epigenetic regulation; hydrophilicity; immunoregulation; infancy; innovation; liver transplantation; metabolomics; monocyte; new therapeutic target; novel; prognostic; programs; recruit; single nucleus RNA-sequencing; survival prediction; total measurement Bilirubin; transcriptional reprogramming; treatment strategy; uptake

Biliary atresia (BA) is a cholestatic liver disease of infancy and is the leading cause of pediatric liver transplantation. Current evidence supports the principle that BA arises from an aberrant immune response to an environmental trigger. However, the exact mechanism of disease remains unknown. While macrophages (M) have been implicated in both human and murine BA, M are heterogeneous by nature and the metabolic networks responsible for pro-restorative vs pro- inflammatory M polarization have not been defined. Our central premise is that identifying macrophage-specific immune-metabolic signatures associated with patient outcome will lead to novel prognostic biomarkers and cell-subset specific therapies to prolong transplant-free survival. We have been the first to identify a prognostic metabolite signature in BA infants at the time of diagnosis. We have shown that distinct changes in serum arginine metabolites, particularly increased polyamines, in BA infants at the time of diagnosis was associated with increased survival with native liver (SNL) at the age of 2 years despite no baseline differences in clinical characteristics. Polyamines are known to reprogram M to an anti-inflammatory phenotype, in part through efferocytosis (i.e. apoptotic cell uptake). Our preliminary data found that BA patients with a polyamine-high metabolic signature had increased hepatic numbers of previously characterized monocyte-like M (MLM, increased expression for genes associated with monocytes) and serum GM-CSF. We thereby hypothesize that recruited MLM promote hepatic adaptation to biliary obstruction; thus, metabolic and epigenetic reprogramming of MLM towards and anti-inflammatory phenotype will be associated with SNL at 2 years of age. To investigate this hypothesis, we will: 1) define the prognostic role for serum arginine metabolites, and 2) identify cell subset specific transcriptional phenotypes associated with SNL.

胆道闭锁（BA）是一种婴儿期胆汁淤积性肝病，是小儿胆汁淤积性肝病的主要原因 肝移植。目前的证据支持 BA 源自异常的原则 对环境触发因素的免疫反应。然而，疾病的确切机制仍然存在 未知。虽然巨噬细胞 (M) 与人类和小鼠 BA 都有关联，但 M 是 本质上是异质的，代谢网络负责促进恢复与促进恢复 炎症 M 极化尚未定义。我们的中心前提是识别 与患者结果相关的巨噬细胞特异性免疫代谢特征将导致 新的预后生物标志物和细胞亚群特异性疗法可延长无移植生存期。 我们是第一个在 BA 婴儿中鉴定出预后代谢特征的人 诊断。我们已经证明血清精氨酸代谢物的明显变化，特别是 BA 婴儿在诊断时的多胺含量增加与 尽管临床基线没有差异，但 2 岁时的天然肝脏存活率 (SNL) 特征。已知多胺可将 M 重新编程为抗炎表型， 部分通过胞吞作用（即凋亡细胞摄取）。我们的初步数据发现 BA 患者 具有多胺高代谢特征的人先前的肝脏数量增加 特征为单核细胞样 M（MLM，与相关基因的表达增加 单核细胞）和血清 GM-CSF。因此，我们假设招募的传销促进肝脏 适应胆道梗阻；因此，MLM 的代谢和表观遗传重编程 抗炎表型将与 2 岁时的 SNL 相关。调查 根据这一假设，我们将：1) 定义血清精氨酸代谢物的预后作用，以及 2) 识别与 SNL 相关的细胞亚群特异性转录表型。