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脏疾病，是儿童胆汁淤积性肝脏疾病的主要原因