Targeted gene disruptions in the iqgap2 gene
AssigneeThe Research Foundation of State University of New York
InventorsValentina Schmidt, Wadie F. Bahou
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Abstract
The invention provides a non-human mammal or a cell line that has a targeted gene disruption in an endogenous Iqgap2 gene. The invention also provides methods of identifying a compound as a therapeutic agent for the treatment of hepatocellular carcinoma and methods of treating or preventing hepatocellular carcinoma.
Claims52
A non-human mammal, which comprises a targeted gene disruption in an endogenous Iqgap2 gene.
A non-human mammal, which comprises a transgene that encodes an RNA that inhibits expression of an endogenous Iqgap2 gene.
A non-human mammal, which comprises a transgene that overexpresses an Iqgap1 gene.
A cell line which comprises an inactivated endogenous Iqgap2 gene.
A targeting construct comprising a first polynucleotide sequence homologous to a first portion of an endogenous Iqgap2 gene, a second polynucleotide sequence homologous to a second portion of the endogenous Iqgap2 gene, and a selectable marker located between the first and second polynucleotide sequences.
A method of producing a transgenic non-human mammal comprising a disruption in an endogenous Iqgap2 gene, comprising:
- a) introducing a targeting construct capable of disrupting the endogenous Iqgap2 gene into an embryonic stem cell of the mammal;
- b) selecting an embryonic stem cell that has undergone homologous recombination
- c) introducing the recombinant embryonic stem cell into a blastocyst;
- d) implanting the blastocyst into the mammal, wherein the mammal gives birth to a chimeric mammal;
- and
- e) breeding the chimeric mammal to produce the transgenic mammal,
- wherein when the disruption is homozygous, the transgenic mammal lacks production of a functional IQGAP2 protein.
A method of identifying a compound as a therapeutic agent for the treatment of hepatocellular carcinoma, comprising:
- contacting the compound with a test cell that underexpresses Iqgap2, wherein Iqgap1 is overexpressed, and
- identifying the compound as a therapeutic agent for treatment of hepatocellular carcinoma if IQGAP1 activity is reduced in response to the compound.
A method of identifying a compound as a therapeutic agent for the treatment of hepatocellular carcinoma, comprising:
- contacting the compound with a test cell that overexpresses Iqgap1, and
- identifying the compound as a therapeutic agent for treatment of hepatocellular carcinoma if IQGAP1 activity is reduced in response to the compound.
A method of identifying a compound as a therapeutic agent for the treatment of hepatocellular carcinoma, comprising:
- providing a non-human mammal which comprises a targeted gene disruption in an endogenous Iqgap2 gene and exhibits an age-dependent increase in apoptosis of hepatocytes;
- administering the compound to the non-human mammal, and
- identifying the compound as a therapeutic agent if it reduces the age-dependent increase in apoptosis.
A method of identifying a compound as a therapeutic agent for the treatment of hepatocellular carcinoma, comprising:
- providing a non-human mammal which comprises a targeted gene disruption in an endogenous Iqgap2 gene and exhibits an age-dependent increase in hepatocellular carcinoma;
- administering the compound to the non-human mammal, and
- identifying the compound as a therapeutic agent if it reduces the age-dependent increase in hepatocellular carcinoma.
A model of human hepatocellular carcinoma comprising hepatocytes in which Iqgap2 is underexpressed.
A method of treating or preventing hepatocellular carcinoma comprising administering an agent that decreases Iqgap1 function in hepatocytes.
A method of treating or preventing hepatocellular carcinoma by administering an agent that enhances Iqgap2 function in hepatocytes.
Dependencies are inferred from the claim text.