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(12) United States Patent (10) Patent No.: US 8,000,949 B2 Nikolskaya Et Al USOO8000949B2 (12) United States Patent (10) Patent No.: US 8,000,949 B2 Nikolskaya et al. (45) Date of Patent: * Aug. 16, 2011 KEGG table of contents as of Feb. 1999, retrieved online at <http:// (54) METHODS FOR IDENTIFICATION OF web.archive.org/web/19990203053246/www.genome.ad.jp/kegg? NOVEL PROTEIN DRUG TARGETS AND kegg2.html>. BOMARKERS UTILIZING FUNCTIONAL Khan et al., Electrophoresis (1999) 2002):223-229. NETWORKS Kirkpatricket al., Gene (1995) 153(2): 147-154. Kuffner et al., Bioinformatics (2000) 16(9):825-836. (75) Inventors: Tatiana Nikolskaya, Portage, IN (US); Kupsch et al., Nervenarzt (1991) 62:80-91. Andrej Bugrim, St. Joseph, MI (US); Kuroda et al., J. Dermatol. Sci. (2001) 26(2):156-160. Yuri Nikolsky, Portage, IN (US) Lindvall, Europ. Neurol. (1991) 31(Suppl. 1):17-27. Lark et al., Fed Proc. (1985) 44(2):394-403. Luke and Prehm, Biochem. J. (1999) 343(Pt. 1):71-75. (73) Assignee: Genego, Inc., Saint Joseph, MI (US) Mookerjea, Can J. Biochem. (1978) 56(7):746-752. Nakao et al., Genome Informatics (1999) 10:94-103. (*) Notice: Subject to any disclaimer, the term of this NCBI Online Database. Accesion Nos. AAE 10146-AAE 10153. patent is extended or adjusted under 35 NCBI Online Database. Accession Nos. AAE13758-AAE 13770. U.S.C. 154(b) by 1266 days. NCBI Online Database. Accession Nos. AAE67749-AAE67785. Neuger et al., Atherosclerosis (2001) 157(1): 13-21. This patent is Subject to a terminal dis Okubo et al., Nature Genetics (1992) 2:173-179. claimer. Osawa et al., Cells Tissues Organs (2000) 167(1):9-17. Papakonstantinou et al., Atherosclerosis (1998) 138(1): 79-89. Papakonstantinou et al., PNAS USA (1995) 92(21).9881-9885. (21) Appl. No.: 11/499.437 Permyakov and Savel Ev, Zh Nevrol Psikhiatr Im S S Korsakova (1998) 98(2):59-61. (22) Filed: Aug. 4, 2006 Recklies et al., Biochem. J. (2001) 354(Pt. 1): 17-24. Saveliev et al., Int J. Biol. 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Vellacott and Balfour, Br. Med J. (1978) 2(6138):699. (51) Int. Cl. Volker et al., J. Histochem. Cytochem. (1991) 39(10): 1385-1394. G06G 7/48 (2006.01) Watanabe and Yamaguchi, J. Biol. Chem. (1996) 271 (38):22945 (52) U.S. Cl. ......................................................... 703/11 22948. (58) Field of Classification Search ........................ None Zimmermann et al., (Biochim. Biophys. Acta (2000) 1484(2-3):316 See application file for complete search history. 324. Covert, Trends in Biochemical Sciences (2001) 26(3): 179-186. Notice of Rejection for Japanese Patent Application No. 2004 (56) References Cited 514229, mailed on Jun. 23, 2009, 3 pages. GOLD Database, retrieved online at http://wit, integratedgenomics. U.S. PATENT DOCUMENTS com/GOLD?, date retrieved on May 23, 2008. 2002/0159625 A1 10/2002 Elling 2003,0224363 A1 12, 2003 Park et al. * cited by examiner 2003/0233218 A1* 12/2003 Schilling ......................... TO3/11 2006/0235624 A1 10/2006 Nikolskaya et al. Primary Examiner — Karlheinz, R Skowronek FOREIGN PATENT DOCUMENTS (74) Attorney, Agent, or Firm — Morrison & Foerster LLP WO WO-OOf 50889 8, 2000 WO WOO1? 13105 * 2/2OO1 (57) ABSTRACT The process of System Reconstruction is used to integrate OTHER PUBLICATIONS sequence data, clinical data, experimental data, and literature Forstet al. (Journal of Computational Biology vol. 6, Nos. 3/4, 1999, into functional models of disease pathways. System Recon pp. 343-360).* struction models serve as informational skeletons for inte Takai-Igarashi et al. (In Silico Biology, vol. 1, p. 129-146, 1999).* grating various types of high-throughput data. The present Ishizuka et al.(Information processing Society of Japan, vol. 91, p. invention provides the first metabolic reconstruction study of 73-80, Sep. 27, 2000).* a eukaryotic organism based solely on expressed sequence Boot et al., Arterioscler Thromb Vasc Biol. (1999) 19(3):687-694. tag (EST) data. System Reconstruction also provides a Chajara et al., Atherosclerosis (1996) 125(2):193-207. ERGO System Database, website retrieval online at <http://igweb. method for the identification of novel therapeutic targets and integratedgenomics.com/IGwit/. biomarkers using network analysis. The initial seed networks Haase and Bartold, J. Periodontol. (2001) 72(3):341-348. are built from the lists of novel targets for diseases with the Hovingh and Linker, J. Biol. Chem. (1970) 245:6170-6175 (EC No. high-throughput experimental data being Superimposed on 4.2.2.7). the seed networks to identify specific targets. Johansen et al., Exp Opin TherTargets (2007) 11(2):219-234. Karp et al., Trends in Biotechnology (1999) 17:275-281. 9 Claims, 75 Drawing Sheets U.S. Patent Aug. 16, 2011 Sheet 1 of 75 US 8,000,949 B2 Figure l Phenotypes Diseases information:Addsystem-level fromtheliteraturepathwayscompiled Human-specific Pathways thathasmanygaps Pathwaysare CompletedFunctional skeletonreconstruction assembledintoa ReConstructionof pathwaystofillingaps Useformalnetworkto amonghypothetical Selectthemostfeasible constructhypothetical pa??º?usingConstraints Regulatory Metabolic KineticPhysical Thermodynamic Constraints: biochemicalreactions|generallyknown assembledfrom Formalnetwork U.S. Patent Aug. 16, 2011 Sheet 2 of 75 US 8,000,949 B2 Figure 2 via2.4.2.1. Glycinecatabolista via1,1,f,103 Threoninecatabºlisrael |-FileEditViewFavo,kesIoo?sHelp ?GenetGo-MicrosoftInternetExplorer· hepatiis carcinornae, 2.0xoglutara?e–) wilsonºsºase.... ?··Tryptophanlutarnate?··.:•.L-6 <f~^viai1314 •*.,'catabolizmi-•• catabolizm via4.1.1.28. Indole-3-açetate U.S. Patent ? eb ?— \© &#? US 8,000,949 B2 ?i ?e^ er,iah-comment plaque formationofatherosclerotic lipoproteidlipaseslowsdown CleavingofLDLandVLDLby chemotactic HCgp-39 bindingwith secretioncytokinescommen| e<,surfacelipoproteidlipase 5vianeparinaseHCgp-39 differentcytokinesaltractmacrophages ?g(heparin+HCgp-39) protectedheparin |-heparinandcellsurfaceheparansulfat+activated <!-->detachedcelllipoproteidlipasefrom 52heparinbindsLipoproteid bindingwithcellsurface lipaseinsteadof 55heparansultat gpHCgp-39and chitotriosidase !secretionsecretion andformatlonof?ognice?|8 Sellsurfacelipoproteidlipase ©degradationbindingwithheparansulfat HCgp-39 stimulatespinocytoslsofLDLandVLDL lipoproteidlipase atherosclerosis,Atherome, Furtherdevelopmentof U.S. Patent Aug. 16, 2011 Sheet 4 of 75 US 8,000,949 B2 Figure 4A Snooth fuscle Cells (Celanigration and adhesion are increased,cell proliferation is reduced. Atherosclerotic plaque growth delay subpopulations of macrophages O 9 U U recycling via hyaluronan hyaluronidase chitooligosac charides as prinners for HA extracellular Probably the cascade is located on a cell membrane of fibroblast and SMC. bud the order matrix of the of enzymes is unknown injured vessel wall U.S. Patent Aug. 16, 2011 Sheet 5 Of 75 US 8,000,949 B2 Figure 4B subpopulations of macrophages Snooth Scle Cells low level of hyaluronah induces proliferation and inhibit cell migration Cof (atherosclerotic plaque grows iosidas chitooligosac charides as SX(N e?tracellular natrix of the Probably the cascade is located on a cell membrane of fibroblast and SAMC, but the order injured vessel of enzymes is unknown wall U.S. Patent Aug. 16, 2011 Sheet 6 of 75 US 8,000,949 B2 çøreoftransmembrune basementmembranecollagens fibrogi?ctin surfacº(cynºecan-as proteoglycan}ofceli HSPG(heparansulfate (57VyVºj fibronectin associutag these theHCgp-39workson hermidesmosomeº U.S. Patent Aug. 16, 2011 Sheet 7 Of 75 US 8,000,949 B2 Figure 6 g g : S. | Los Las - saata server-R t \ rises A. Air W s r x - or a MXR U.S. Patent Aug. 16, 2011 Sheet 8 Of 75 US 8,000,949 B2 Figure 7 ofRNA Stabilization datawhenavallable withdifferenttypesof andisfidedinnetworkofpathways p?ac?dintheexisting SpaceHolderis areknown Onlyinputandoutput Mod?fication Covalent U.S. Patent Aug. 16, 2011 Sheet 9 Of 75 US 8,000,949 B2 Figure 8 3. s s , 3. s s d S s U.S. Patent US 8,000,949 B2 L-Meth?onine PartII:briefschemeofhumanAminoaciddegradation scheme picturetoviewdetalledClickanywhereonthe AAdegradationinhuman?iver U.S. Patent Aug. 16, 2011 Sheet 11 of 75 US 8,000,949 B2 Figure 10 Pathwaypagewithinteractivepathwaydiagram DNA CytosolS'-adenosyl-L-methionin? NOTESClickheretoviewpathwayVIEWO Caes?S'-adenosyl-L-homocysteine~ toviewenzymepages ClickonECnumbers toaccºgsreactionpagesClickonreaction symbols L-methionine/L-serine?ipyrophosphate?2-oxobutanoate/Adenosine/L-cysteinellcyt U.S. Patent Aug. 16, 2011 Sheet 12 Of 75 US 8,000,949 B2 Figure 11 Full view of the pathway diagram DNA containing 5-methylcytosine U.S. Patent Aug. 16, 2011 Sheet 13 Of 75 US 8,000,949 B2 Figure 12A Humangenesassigned: EC2.4.2.13(formerty) AdoMetsynthetase S-Adenosylmethioninesynthetase
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