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University of Maryland Baltimore

University of Maryland Baltimore
Experimental Therapeutics Symposium 2009

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    Ma Ma Presentation Transcript

    • Develop in vivoExperimental Therapeutic Model for Anti-Cancer Research
      Mark (Zhi-Qing) Ma, Ph.D.
    • New Preclinical Models to Improve Predictive Value
      • Heterotransplant model of human tumor xenograft
      • Transgenic mouse mode (Over-expression of oncogene)
      • Gene Knockout mouse model (deletion of tumor suppressor)
    • Concept of Heterotransplants
    • Tumor Genome Analysis
      Pre- and Post Treatment
      intact tumor
      microenvironment
      GeneChip Human Exon 1.0 ST Array
      DNA Methylation Analysis
      other genetic and epigenetic assays
      Genome-Wide Human SNP Array 6.0
    • matched
      matched
      50 mouse models
      Repeatable
      Systematic Preclinical Efficacy Evaluation of Drugs (SPEED)
      CTRL Arm : 50 Pts
      Tx Arm : 50 Pts
      Pathak et al., Am J Trans Res, 2009
    • Transgenic Mouse Lines Over-expressing DNMT3B
      SPC/Δ3B4/IGFP (Δ3B4G)
      DrdI
      DrdI
      NdeI
      NotI
      NotI
      IRES-GFP
      pA+
      SPC promoter
      ΔDNMT3B4
      Geno#1
      Forward
      Geno#1
      Reverse
      Geno#2
      Forward
      Geno#2
      Reverse
      SPC/Δ3B4 del/IGFP (Δ3B4DG)
      DrdI
      DrdI
      NotI
      NdeI
      NotI
      IRES-GFP
      pA+
      SPC promoter
      ΔDNMT3B4 del
      Geno#1
      Forward
      Geno#1
      Reverse
      Geno#2
      Forward
      Geno#2
      Reverse
    • Purification of Transgene fragments for Microinjectin
      SPC/Δ3B4Del/IGFP
      (Δ3B4G)
      SPC/Δ3B4/IGFP
      (Δ3B4G)
      Transgene
      10 kb
      8
      6
      4
      3
      Vector
    • Genotyping Strategy of Transgenic Mice
      Tail DNA + Δ3B4DG
      Tail DNA + Δ3B4DG
      Tail DNA + Δ3B4G
      Tail DNA + Δ3B4G
      100 bp Marker
      1 kB Marker
      Tail DNA
      Tail DNA
      Geno#1
      Geno#2
    • Generation of Conditional Mutant
      Cre
      floxed
      breeding
      ATG
      Promoter
      Cre
      Exon3
      Exon2
      Tissue Specific
      Conditional KO mice
    • Generation of FloxedHuR Mouse Line
      5 ARM
      (5.1KB)
      3 ARM
      (1.7 KB)
      5 ARM probe
      3 ARM probe
      E
      E
      A
      A
      A
      A
      A
      A
      E
      E
      E
      E2
      E1
      E3
      Neo
      PGK-TK
      Targeting Vector
      LoxP
      LoxP
      LoxP
      WT Mutant
      5ARM (Apl I) 10.0kb 11.3kb
      3ARM (EcoRI) 5.5kb 7.5kb