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(12) Patent Application Publication (10) Pub. No.: US 2006/0134629 A1 Link Et Al US 2006O134629A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2006/0134629 A1 Link et al. (43) Pub. Date: Jun. 22, 2006 (54) METHODS AND COMPOSITIONS FOR Related U.S. Application Data ELUCDATING PROTEN EXPRESSION PROFILES IN CELLS (63) Continuation-in-part of application No. 09/811,842, filed on Mar. 19, 2001, now Pat. No. 6,897,020. (76) Inventors: Charles J. Link, West Des Moines, IA (US); Tatiana Seregina, West Des (60) Provisional application No. 60/190,678, filed on Mar. Moines, IA (US); Nicholas N. 20, 2000. Provisional application No. 60/458,152, Vahanian, Ankeny, IA (US); James N. filed on Mar. 27, 2003. Higginbotham, Nashville, TN (US); William Jay Ramsey, Ankeny, IA Publication Classification (US); Bradley J. Powers, Ames, IA (US); Sachet A. Shukla, Ames, IA (51) Int. C. (US); Won Bin Young, Des Moines, IA CI2O I/68 (2006.01) (US); Teresa Dicolandrea, Ames, IA G0IN 33/567 (2006.01) (US); Mario R. Mautino, Ankeny, IA GOIN 33/53 (2006.01) (US) (52) U.S. Cl. .................................................. 435/6; 435/7.2 Correspondence Address: ABSTRACT HOWREY LLP (57) CFO IP DOCKETING DEPARTMENT 2941 FAIRVIEW PARK DR, SUITE 200 The present invention relates generally to methods and compositions for the identification of differential protein FALLS CHURCH, VA 22042-2924 (US) expression patterns and concomitantly the active genetic (21) Appl. No.: 10/660,893 regions that are directly or indirectly involved in different tissue types, disease states, or other cellular differences (22) Filed: Sep. 12, 2003 desirable for diagnosis or for targets for drug therapy. Patent Application Publication Jun. 22, 2006 Sheet 1 of 41 US 2006/0134629 A1 - direction of transcription SA SD Marker ExOn RE Splicing Vy SA SD Marker Exon RE Fig. 1 Patent Application Publication Jun. 22, 2006 Sheet 2 of 41 US 2006/0134629 A1 SA NeoR (CNY Marke Gene RE Fig. 2A SA NeoR (CMY Market Gene RE Fig. 2B lake (RS Net ISA RE Fig. 2C SD SA NeoR KCMY Market I RE RE Fig. 2D SA SLIR)-gag | poliew pa Fig. 2E RE SA pA NeoRKCMY Marker Gene 2 Marker Gener - RE Fig.2F Patent Application Publication Jun. 22, 2006 Sheet 3 of 41 US 2006/0134629 A1 'LTR 5 9a9 RRE cPPT hrGFP 3'LTR-SN pHSG 3. i:33Sassa GS Linker 5'LTR gag RRE cPPT hrCFP 3'LTR-SN pHSGEX SEg: Ee-Ed GS Linkers - RRE cPP /GFP \ 3LR-SIN SD SA GS Linkers pHS2ACGEX3 Ad2MLPSD/intron T7 promoter - GS Linker \ 'LTR gag RRE cPPT pUC ori P pHS3ACGEX4 E. S s 3'LTR-SN Patent Application Publication Jun. 22, 2006 Sheet 4 of 41 US 2006/0134629 A1 pHS2GEX3PA CPPT OGa PGK hrCFP 3'LTR-SN A SD,\, GS Linkers/ SA pHS3ACGEX4PA Ad2MLPSD/intron T7 promoter GS Linker 5'LTR gag RRE cRPT C-Gal PGK | AcGFP) Amp pUC ori p SD SA 3'LTR-SN pHS3ACGEX4E1bA Ad2MLPSD/intron T7 promoter AdE1b Promoter GS Linker 5'LTR gag RRE cPPT O-Gal Amp pUC ori P SA 3'LTR-SN pHS3ACGEX4E1bNeo Ad2MLPSD/intron T7 promoter AdE1b PrOnOter GS Linker 5'LTR gag RRE cFPT Neo 3'LTR-SIN Patent Application Publication Jun. 22, 2006 Sheet 5 of 41 US 2006/0134629 A1 enw HA-ExOn HA-FO HA-FO HA-FO - 5'LTR gag RRE pHS2HA3XfO 3'LTR-SIN HA-Exon HA-F1 HA-F1 HA-F1 pHS2HS2 HA3xf 5'LTR Gag RRE CPPT / 3'TR-SN Fig 2i Patent Application Publication Jun. 22, 2006 Sheet 6 of 41 US 2006/0134629 A1 hrCFP 3 - TCGACCCTG GA-5 AlaproVal 3 - TCGCCCTG GA-5 AlaPro BGH pA higF F SA 3' LTR 3'-TCGCCCTGIGA-5' GnSer Fig 2j Patent Application Publication Jun. 22, 2006 Sheet 7 of 41 US 2006/0134629 A1 pGT-fs0 pGT-fs1 pGT-fs2 3 - TCGCCCTGGA-5' GlinSer Fig 2k Patent Application Publication Jun. 22, 2006 Sheet 8 of 41 US 2006/0134629 A1 (SN ACG Patent Application Publication Jun. 22, 2006 Sheet 9 of 41 US 2006/0134629 A1 N- as’ 5 LTR bovine growth hormone poly(A) Fig. 4A ors 5LIR)-pKe:RCW H(hGP SAH ITRD3. Fig. 4B Patent Application Publication Jun. 22, 2006 Sheet 10 of 41 US 2006/0134629 A1 Fig. 5A SA pGTSAH (LTR)-pAKNeoRCMY HHsKhIGFP H. LTR) Fig.5B Patent Application Publication Jun. 22, 2006 Sheet 11 of 41 US 2006/0134629 A1 Patent Application Publication Jun. 22, 2006 Sheet 12 of 41 US 2006/0134629 A1 SA SD hiGFP -ZeoR -( SV40 RE y Transcription SA SD hGFP y Splicing SA SD hrGFP ZeoR RE IrOnslotion GFP - Positive Cells Fig. 7A Un-transfected cells pCT52-Transfected cells "Ink" R. Fig. 7B Patent Application Publication Jun. 22, 2006 Sheet 13 of 41 US 2006/0134629 A1 2: AF rSir od (-) population (+) population PA37 without trGnsfection i"i" is Fig. 8A 2 AF s GFP (-) population CFP (+) population PA317 without trCnsfection O carria"-i" is Fig. 8B Patent Application Publication Jun. 22, 2006 Sheet 14 of 41 US 2006/0134629 A1 kb Fig, 9 Patent Application Publication Jun. 22, 2006 Sheet 15 of 41 US 2006/0134629 A1 3: DF r CN "i" is Fig OA 5: DF Sp s "gig" of Fig OB Patent Application Publication Jun. 22, 2006 Sheet 16 of 41 US 2006/0134629 A1 CO CO Un-transduced NH3T3 cells pGT5Z-Transduced NH3T3 cells rig" of Fig. 1 Patent Application Publication Jun. 22, 2006 Sheet 17 of 41 US 2006/0134629 A1 Cd d . Cld st " .." is - Log CFP 1000 A6P1 C4P2 s S3 L09 FITC 1OOO Log FITC 1 OOO C3P2 HBP2 Un-transduced NH3T3 cells Single-cell clones of transduced NH35 cells Fig 12 Patent Application Publication Jun. 22, 2006 Sheet 18 of 41 US 2006/0134629 A1 SA 3. pGTA (LTRX-pAKNeckS City -(a 13-gal (IR) pGTAH (LIR)-pAKNeoRCNHHisS KatagalSA LIR) 5 SA SD pGT2 (LIR)-pakNeck CW-(a 3-gal-KeoRSYOH LTR) Fig. 13A d 2: AF 2 AF | " ":" is re-In" is Fig. 13B 2: AF Fig, 13C s "-n" to Fig. 3D Patent Application Publication Jun. 22, 2006 Sheet 19 of 41 US 2006/0134629 A1 Specimen 001-HMEC Control 50 100 150 200 250 FITC-A (x 1,000) Specimen 001-HMEC GTFSO Enriched GFP pool 50 00 50 200 250 FTC-A Specimen 001-HMEC CPSA SO 00 150 200 250 FITC-A (x 1,000) Specimen 001-HMEC D. PSA 50 100 150 FTC-A (x 1,000) Specimen 001-HMEC E PSA 100 50 2OO FITC-A Specimen 001-HMEC FPSA Patent Application Publication Jun. 22, 2006 Sheet 20 of 41 US 2006/0134629 A1 Specimen 001-MCF 7 Control 50 100 150 200 (x1,000)250 FTC-A Specimen OO1-MCF 7 GTFSO DPSA 50 100 50 200 250 FITC-A (x1,000) Specimen OO1-MCF 7 GTFSO EPSA 200 250 FTC-A (x1,000) Patent Application Publication Jun. 22, 2006 Sheet 21 of 41 US 2006/0134629 A1 Specimen 001-MM HMEC control 50 100 150 20 250 FITC-A (x 1,000) Specimen 001-HSGHMEC enriched GFP pool 50 100 150 200 (x1,000)250 FITC-A 50 100 150 200 250 FTC-A 100 150 200 250 50 FITC-A - 200 250 FITCA Patent Application Publication Jun. 22, 2006 Sheet 22 of 41 US 2006/0134629 A1 14D Specimen 001-Control MCF7 50 100 150 200 250 FITC-A (xi,000) Specimen 001-MCF7 HSG Enriched GFP pool 50 100 50 200 250 50 100 150 200 250 FITC-A (x1,000) 50 00 150 200 250 FTC-A (x1,000) Specimen 001-MCF7 HSGE gate PSA 50 100 150 200 250 FC-A (x1,000) 50 100 150 200 250 FTC-A (xf,000) Patent Application Publication Jun. 22, 2006 Sheet 23 of 41 US 2006/0134629 A1 Notural genomic structure fbp added to change reading frome 2bp added to change reoding frame Markers Fig 15 Patent Application Publication Jun. 22, 2006 Sheet 24 of 41 US 2006/0134629 A1 A SA Act 3LTR Restriction enzyme digestion, Such Acil (Is Act Aci Self-ligation --Primer 2 Aci y PCR amplification Primer Primer 2 Fractional Separation y Sequencing y Blasting search on EST Of genomic database Gene Exprssion Profiting Databases On target cells vs. Counterpart Fig, 16 Patent Application Publication Jun. 22, 2006 Sheet 25 of 41 US 2006/0134629 A1 SA SD SD Marker Gene The Kasha RE Chromosomol DNA y TronScription SA SD Marker Gene 4ExOn Pre-moture RNA RE y Splicing SA SD Marker Gene Exon mRNA RE cDNA Synthesis RE Digestion SA SD . In RNA Af Fig. 17A Patent Application Publication Jun. 22, 2006 Sheet 26 of 41 US 2006/0134629 A1 SA SD Marker Geneo Single-stranded DNA extension Poly-T toiling reoction of Toiling by Terminol Tronsferose SA SD Poly-T tail RE PCR amplification with marker gene-specific primer and oligo dT(25-35) primer y Ligation SA SD SA S SA SO Poly-T tail Marker Gene Eton Poly-T tail Poly-T to: RE RE RE y Sequencing y Blasting search on EST or genomic database Gene Expression Profiling Database on target cells vs. counterpart Fig, 17B Patent Application Publication Jun. 22, 2006 Sheet 27 of 41 US 2006/0134629 A1 PROCESS STEP EXAMPLES Cell Set Colon concer/vs. normal Colon Cells Or lung Concer /.S. normal lung epithelium youngOf Organism cell set/vs. old Organism cell set Vextor Tag MMLYhCFP w/ a(13)galactosyltransferaseO O DNA transfection MeOSurement FACS SCOn for hrCFP Florescence Of ELISA for hrCFP protein | FACSOr Scan for a (1.5GT induced a-gol Ag O EUSA of a(3)GT protein 0.
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