Immune-Metabolic Regulation of Biliary Atresia

胆道闭锁的免疫代谢调节

基本信息

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
项目类别：
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

项目摘要

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）是婴儿期的胆固性肝病，是小儿的主要原因肝移植。当前的证据支持BA源于异常的原则对环境触发的免疫反应。但是，疾病的确切机制仍然存在未知。尽管人和鼠ba中都隐含了巨噬细胞（M），但m是本质上是异质的，以及负责利率与利益的代谢网络尚未定义炎症M极化。我们的中心前提是确定与患者结局相关的巨噬细胞特异性免疫代谢特征将导致新型的预后生物标志物和细胞 - 亚木特异性疗法可延长无移植生存。我们是第一个在BA婴儿中确定预后代谢物签名的人诊断。我们已经表明，血清精氨酸代谢产物的明显变化，特别是诊断时BA婴儿的多胺增加与增加有关 2岁时，有天然肝（SNL）生存特征。已知多胺将m重新编程为抗炎表型，在通过肿瘤病（即凋亡细胞摄取）的一部分。我们的初步数据发现BA患者多胺高代谢特征的肝脏数量增加了以前表征单核细胞样M（MLM，与与之相关的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MLM促进肝适应胆道异议；因此，MLM的代谢和表观遗传重编程抗炎表型将在2岁时与SNL有关。调查这个假设，我们将：1）定义血清精氨酸代谢产物的预后作用，以及2）识别与SNL相关的细胞子集特异性转录表型。