Min Jun, Ningappa Mylarappa, So Juhoon, Shin Donghun, Sindhi Rakesh, Subramaniam Shankar
Department of Bioengineering, University of California, San Diego, La Jolla, CA, United States.
Hillman Center for Pediatric Transplantation, Children's Hospital of Pittsburgh of University of Pittsburgh Medical Center (UPMC), Pittsburgh, PA, United States.
Front Physiol. 2020 Aug 7;11:966. doi: 10.3389/fphys.2020.00966. eCollection 2020.
Biliary atresia (BA), blockage of the proper bile flow due to loss of extrahepatic bile ducts, is a rare, complex disease of the liver and the bile ducts with unknown etiology. Despite ongoing investigations to understand its complex pathogenesis, BA remains the most common cause of liver failure requiring liver transplantation in children. To elucidate underlying mechanisms, we analyzed the different types of high-throughput genomic and transcriptomic data collected from the blood and liver tissue samples of children suffering from BA. Through use of a novel integrative approach, we identified potential biomarkers and over-represented biological functions and pathways to derive a comprehensive network showing the dysfunctional mechanisms associated with BA. One of the pathways highlighted in the integrative network was hypoxia signaling. Perturbation with hypoxia inducible factor activator, dimethyloxalylglycine, induced the biliary defects of BA in a zebrafish model, serving as a validation for our studies. Our approach enables a systems-level understanding of human BA biology that is highlighted by the interaction between key biological functions such as fibrosis, inflammation, immunity, hypoxia, and development.
胆道闭锁（BA）是一种罕见且复杂的肝脏和胆管疾病，病因不明，是由于肝外胆管缺失导致胆汁正常流动受阻。尽管一直在进行研究以了解其复杂的发病机制，但BA仍然是儿童肝衰竭需要肝移植的最常见原因。为了阐明潜在机制，我们分析了从患有BA的儿童的血液和肝组织样本中收集的不同类型的高通量基因组和转录组数据。通过使用一种新颖的综合方法，我们确定了潜在的生物标志物以及过度表达的生物学功能和途径，以构建一个全面的网络，展示与BA相关的功能失调机制。综合网络中突出显示的途径之一是缺氧信号传导。在斑马鱼模型中，用缺氧诱导因子激活剂二甲基草酰甘氨酸进行干扰，可诱发BA的胆管缺陷，这为我们的研究提供了验证。我们的方法能够从系统层面理解人类BA生物学，其特点是纤维化、炎症、免疫、缺氧和发育等关键生物学功能之间的相互作用。
