title: Integrative biological analysis of the APOE*3-leiden transgenic mouse.
abstract: 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.
authors.affiliation: Beyond Genomics, Inc., Waltham, Massachusetts 02451, USA. CClish@BeyondGenomics.com
authors.forename: Clary B
authors.initials: CB
authors.lastname: Clish
authors.forename: Eugene
authors.initials: E
authors.lastname: Davidov
authors.forename: Matej
authors.initials: M
authors.lastname: Oresic
authors.forename: Thomas N
authors.initials: TN
authors.lastname: Plasterer
authors.forename: Gary
authors.initials: G
authors.lastname: Lavine
authors.forename: Tom
authors.initials: T
authors.lastname: Londo
authors.forename: Michael
authors.initials: M
authors.lastname: Meys
authors.forename: Philip
authors.initials: P
authors.lastname: Snell
authors.forename: Wayne
authors.initials: W
authors.lastname: Stochaj
authors.forename: Aram
authors.initials: A
authors.lastname: Adourian
authors.forename: Xiang
authors.initials: X
authors.lastname: Zhang
authors.forename: Nicole
authors.initials: N
authors.lastname: Morel
authors.forename: Eric
authors.initials: E
authors.lastname: Neumann
authors.forename: Elwin
authors.initials: E
authors.lastname: Verheij
authors.forename: Jack T W E
authors.initials: JT
authors.lastname: Vogels
authors.forename: Louis M
authors.initials: LM
authors.lastname: Havekes
authors.forename: Noubar
authors.initials: N
authors.lastname: Afeyan
authors.forename: Fred
authors.initials: F
authors.lastname: Regnier
authors.forename: Jan
authors.initials: J
authors.lastname: van der Greef
authors.forename: Stephen
authors.initials: S
authors.lastname: Naylor
mesh_terms: D000818:Animals; D053318:Apolipoprotein E3; D001057:Apolipoproteins E / Q000235:genetics* / Q000502:physiology*; D001161:Arteriosclerosis / Q000378:metabolism; D002352:Carrier Proteins / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid; D002853:Chromatography, Liquid; D050556:Fatty Acid-Binding Proteins; D016678:Genome; D006801:Humans; D050356:Lipid Metabolism; D008099:Liver / Q000378:metabolism; D008244:Lysophosphatidylcholines / Q000378:metabolism; D013058:Mass Spectrometry; D051379:Mice; D008822:Mice, Transgenic; D008954:Models, Biological; D015999:Multivariate Analysis; D020411:Oligonucleotide Array Sequence Analysis; D012313:RNA / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism; D014357:Trypsin / Q000378:metabolism / Q000494:pharmacology
chemical_list: D053318:Apolipoprotein E3; D001057:Apolipoproteins E; D002352:Carrier Proteins; C493319:FABP1 protein, human; C493320:Fabp1 protein, mouse; D050556:Fatty Acid-Binding Proteins; D008244:Lysophosphatidylcholines; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D014157:Transcription Factors; C052720:apolipoprotein E3 (Leidein); D012313:RNA; D014357:Trypsin