Integrative biological analysis of the APOE*3-Leiden transgenic mouse
Integrative biological analysis of the APOE*3-Leiden transgenic mouse
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DOI：
10.1089/153623104773547453
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发表时间：
2004-03-01
影响因子：
3.3
通讯作者：
Naylor, S
中科院分区：
文献类型：
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作者：
Clish, CB;Davidov, E;Naylor, S
整合（或系统生物学）是一种新的方法来分析生物实体作为遗传，基因组，蛋白质，代谢物，细胞和途径事件的整合系统，这些事件是不断变化和相互依赖的。在这里，我们展示了整合生物学分析的哺乳动物疾病模型，载脂蛋白E3-莱顿（APO*E3）转基因小鼠的应用。选择用于研究的小鼠喂食正常的食物，并在9周龄时处死，在这种条件下，它们仅发生轻度的I型和II型动脉粥样硬化病变。肝脏mRNA表达分析显示，转基因和野生型对照小鼠之间，载脂蛋白A1降低25%，肝脏脂肪酸结合蛋白表达增加43%，而PPAR-alpha表达无变化。在线高效液相色谱-质谱法定量分析可溶性肝蛋白和肝脂质的胰蛋白酶，再加上主成分分析，使快速识别早期蛋白质和代谢物标志物的疾病病理。这些包括与对照组相比，转基因动物中L-FABP增加44%，以及甘油三酯和选择的生物活性溶血磷脂酰胆碱种类增加。一个相关性分析确定的基因，蛋白质和脂质被用来构建一个相互作用网络。总之，这些结果表明，整合生物学是一个强大的工具，快速识别早期标记和病理生理过程的关键组成部分，并构成了这种方法的第一次应用于哺乳动物系统。
Integrative (or systems biology) is a new approach to analyzing biological entities as integrated systems of genetic, genomic, protein, metabolite, cellular, and pathway events that are in flux and interdependent. Here, we demonstrate the application of intregrative biological analysis to a mammalian disease model, the apolipoprotein E3-Leiden (APO*E3) transgenic mouse. Mice selected for the study were fed a normal chow diet and sacrificed at 9 weeks of age-conditions under which they develop only mild type I and II atherosclerotic lesions. Hepatic mRNA expression analysis showed a 25% decrease in APO A1 and a 43% increase in liver fatty acid binding protein expression between transgenic and wild type control mice, while there was no change in PPAR-alpha expression. On-line high performance liquid chromatography-mass spectrometry quantitative profiling of tryptic digests of soluble liver proteins and liver lipids, coupled with principle component analysis, enabled rapid identification of early protein and metabolite markers of disease pathology. These included a 44% increase in L-FABP in transgenic animals compared to controls, as well as an increase in triglycerides and select bioactive lysophosphatidylcholine species. A correlation analysis of identified genes, proteins, and lipids was used to construct an interaction network. Taken together, these results indicate that integrative biology is a powerful tool for rapid identification of early markers and key components of pathophysiologic processes, and constitute the first application of this approach to a mammalian system.