使用大鼠基因组规模代谢模型量化剂量依赖化学物质暴露的肝毒性反应
Venkat R Pannala1,2, Archana Hari1,2, Mohamed Diwan M AbdulHameed1,2
1Department of Defense Biotechnology High Performance Computing Software Applications Institute, Telemedicine and Advanced Technology Research Center, U.S. Army Medical Research and Development Command, Fort Detrick, MD 21702, United States.
概括
这项研究开发了一种系统生物学方法,整合了老鼠代谢模型和转录组学数据,以识别由肝毒化学物质改变的基因特征和代谢途径. 这种方法区分了有毒剂诱导的肝损伤与非有毒化学效应.
科学领域:
- 毒理学 毒理学 毒理学
- 代谢学 代谢学 代谢学
- 系统生物学 系统生物学
背景情况:
- 肝脏在化学清除中的作用使其易受毒性影响.
- 目前的转录学等方法提供基因级数据,但需要系统级的解释.
- 动物试验是评估化学肝毒性的标准.
研究的目的:
- 开发和应用一个系统层面的方法来解释转录组学数据在化学诱导的肝毒性.
- 确定基因表达模式和代谢途径,区分肝毒性和非毒性化学物质暴露.
- 通过综合代谢建模和转录学来理解肝毒性的机制.
主要方法:
- 开发了一个更新的老鼠基因组规模的代谢模型.
- 综合大规模的转录组学数据来自体内大鼠研究.
- 使用基于化学结构相似性的ToxProfiler工具来识别毒性目标.
- 分析了非毒性和肝毒性化学物质暴露之间的差异性基因表达和途径改变.
主要成果:
- 鉴定出不同的基因表达模式,与非有毒化学物质相比,肝毒药能调高大多数基因.
- 发现对肝毒化学物质的碳水化合物,氨基酸和脂质代谢途径的显著上调.
- 使用综合模型,由肝毒性与非毒性化学物质系统上升或抑制的差异化代谢物.
结论:
- 综合系统生物学方法成功识别了基因签名,这些基因签名可以区分肝脏的毒性反应.
- 这种方法突出了潜在的代谢途径和代谢物,这些代谢物与有毒物质暴露系统相关.
- 为了解化学诱导的肝毒性机制提供了一个框架.
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