Fecho Karamarie, Tucker Nyssa, Beasley Jon-Michael, Auerbach Scott S, Bizon Chris, Tropsha Alexander
Renaissance Computing Institute, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States.
Copperline Professional Solutions, LLC, Pittsboro, NC, United States.
Front Toxicol. 2025 Apr 22;7:1549268. doi: 10.3389/ftox.2025.1549268. eCollection 2025.
We developed the Reasoning Over Biomedical Objects linked in Knowledge Oriented Pathways (ROBOKOP) application as an open-source knowledge graph system to support evidence-based biomedical discovery and hypothesis generation. This study aimed to apply ROBOKOP to suggest biological mechanisms that might explain the hypothesized relationship between exposure to the herbicide and lipid-lowering drug clofibrate, an activator of peroxisome proliferator-activated receptor-α (PPARA), and hepatic fibrosis. We queried ROBOKOP to first establish that it could demonstrate a relationship between clofibrate and PPARA as a validation test and second to identify intermediary genes and biological processes or activities that might relate the activation of PPARA by clofibrate to hepatic fibrosis. Queries of ROBOKOP returned several paths relating clofibrate, PPARA, and hepatic fibrosis. One path suggested the following: . This result established a relationship between clofibrate and PPARA and further suggested that PPARA is actively involved in the cellular response to lipids, which actively involves the chemokine ligand CCL2, a gene genetically associated with hepatic fibrosis; thus, we can infer that PPARA, upon activation by clofibrate, plays a role in hepatic fibrosis. We conclude that ROBOKOP can be used to derive insights into biological mechanisms that might explain relationships between environmental exposures and liver toxicity.
我们开发了“基于知识导向路径的生物医学对象推理”（ROBOKOP）应用程序，作为一个开源知识图谱系统，以支持基于证据的生物医学发现和假设生成。本研究旨在应用ROBOKOP来提出可能解释除草剂暴露与降脂药物氯贝丁酯（一种过氧化物酶体增殖物激活受体-α（PPARA）的激活剂）和肝纤维化之间假设关系的生物学机制。我们查询ROBOKOP，首先确定它能否证明氯贝丁酯与PPARA之间的关系作为验证测试，其次识别可能将氯贝丁酯对PPARA的激活与肝纤维化联系起来的中间基因以及生物学过程或活动。对ROBOKOP的查询返回了几条将氯贝丁酯、PPARA和肝纤维化联系起来的路径。其中一条路径表明如下：…… 这一结果确立了氯贝丁酯与PPARA之间的关系，并进一步表明PPARA积极参与细胞对脂质的反应，而这一反应积极涉及趋化因子配体CCL2，一个与肝纤维化存在基因关联的基因；因此，我们可以推断，氯贝丁酯激活后的PPARA在肝纤维化中发挥作用。我们得出结论，ROBOKOP可用于深入了解可能解释环境暴露与肝脏毒性之间关系的生物学机制。
