Immune-Metabolic Regulation of Biliary Atresia

胆道闭锁(BA)是一种婴幼儿胆汁淤积性肝病，是儿童胆汁淤积性肝病的主要病因。 肝脏移植。目前的证据支持BA起源于一种异常的原理 对环境触发的免疫反应。然而，疾病的确切机制仍然存在。 未知。巨噬细胞(M)在人类和小鼠的BA中都有牵连，而M则是 本质上是异质性的，代谢网络负责促进恢复与促进 炎症性M-极化尚未定义。我们的中心前提是识别 与患者预后相关的巨噬细胞特异性免疫代谢特征将导致 新的预后生物标记物和细胞亚群特异性治疗延长无移植生存期。 我们首次在BA婴儿中发现了一个预后代谢物信号 诊断。我们已经证明，血清精氨酸代谢产物的明显变化，尤其是 诊断时BA婴儿的多胺增加与增加有关 尽管临床上没有基线差异，但2岁时有天然肝脏(SNL)的存活率 特点。已知多胺可将M重新编程为抗炎表型，在 部分通过胞吐作用(即细胞凋亡摄取)。我们的初步数据发现，BA患者 具有多胺高代谢特征的患者以前的肝脏数量增加 特征为单核细胞样M(MLM)，与以下相关基因表达增加 单核细胞)和血清GM-CSF。因此，我们假设招募的传销促进肝脏 对胆道梗阻的适应；因此，MLM的代谢和表观遗传重新编程 抗炎表型在2岁时与SNL相关。去调查 这一假设，我们将：1)定义血清精氨酸代谢产物的预后作用，以及2) 鉴定与SNL相关的细胞亚群特异性转录表型。

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.