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Ma

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University of Maryland Baltimore …

University of Maryland Baltimore
Experimental Therapeutics Symposium 2009

Published in: Education, Technology
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Transcript

  • 1. Develop in vivoExperimental Therapeutic Model for Anti-Cancer Research
    Mark (Zhi-Qing) Ma, Ph.D.
  • 2. New Preclinical Models to Improve Predictive Value
    • Heterotransplant model of human tumor xenograft
    • 3. Transgenic mouse mode (Over-expression of oncogene)
    • 4. Gene Knockout mouse model (deletion of tumor suppressor)
  • Concept of Heterotransplants
  • 5. 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
  • 6. 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
  • 7. 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
  • 8. Purification of Transgene fragments for Microinjectin
    SPC/Δ3B4Del/IGFP
    (Δ3B4G)
    SPC/Δ3B4/IGFP
    (Δ3B4G)
    Transgene
    10 kb
    8
    6
    4
    3
    Vector
  • 9. 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
  • 10. Generation of Conditional Mutant
    Cre
    floxed
    breeding
    ATG
    Promoter
    Cre
    Exon3
    Exon2
    Tissue Specific
    Conditional KO mice
  • 11. 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

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