MULTIPLE INDUCIBLE GENE REGULATION SYSTEM

1 - 20 . (canceled)

21 . An inducible gene expression modulation system comprising at least two orthogonal gene switches that control expression of at least two genes of interest, the system comprising:

at least two gene switches, wherein each gene switch comprises a fusion protein; and

at least two ligands, wherein at least one of the ligands is a diacylhydrazine.

22 . The inducible gene expression modulation system of claim 21 , wherein the system is used in mammalian gene therapy applications.

23 . The inducible gene expression modulation system of claim 21 , wherein expression of at least one gene switch is driven by a tissue-specific promoter.

24 . An inducible gene expression modulation system comprising at least two orthogonal gene switches that control expression of at least two genes of interest, wherein each gene switch is activated by a different ligand, and wherein each gene switch comprises:

a gene expression cassette comprising a promoter operably linked to a polynucleotide that encodes a fusion protein, wherein the fusion protein comprises a DNA-binding domain that recognizes a response element associated with a gene of interest, a ligand binding domain comprising at least a portion of a Group H nuclear receptor ligand binding domain;

wherein the DNA-binding domain is from a nuclear receptor other than a Group H nuclear receptor.

25 . The inducible gene expression modulation system according to claim 24 , wherein the Group H nuclear receptor is an ecdysone receptor.

26 . The inducible gene expression modulation system of claim 24 , wherein expression of at least one gene switch is driven by a tissue-specific promoter.

27 . The inducible gene expression modulation system of claim 24 , wherein the system is used in mammalian gene therapy applications.

28 . A vector comprising the inducible gene expression modulation system according to claim 24 .

29 . An isolated host cell into which the inducible gene expression modulation system according to claim 24 has been introduced.

30 . The isolated host cell according to claim 29 , wherein the host cell is selected from the group consisting of a bacterial cell, a fungal cell, a yeast cell, a plant cell, an animal cell, a mammalian cell, a mouse cell, and a human cell.

31 . A non-human organism comprising a host cell into which the inducible gene expression modulation system according to claim 24 has been introduced.

32 . The non-human organism according to claim 31 , wherein the non-human organism is selected from the group consisting of a bacterium, a fungus, a yeast, a plant, an animal, and a mammal.

33 . An inducible gene expression modulation system comprising at least two orthogonal gene switches that control tissue-specific expression of at least two genes of interest, wherein each gene switch is activated by a different ligand, and wherein each gene switch comprises the elements of I or II:

I)

a) a first gene expression cassette comprising a tissue-specific promoter operably linked to a polynucleotide sequence that encodes a first polypeptide comprising:

a DNA-binding domain that recognizes a response element associated with a gene of interest; a ligand binding domain comprising at least a portion of a ligand binding domain from a Group H nuclear receptor polypeptide;

b) a second gene expression cassette comprising a tissue-specific promoter operably linked to a polynucleotide sequence that encodes a second polypeptide comprising:

a transactivation domain; and

a ligand binding domain comprising at least a portion of a ligand binding domain from a truncated retinoid X receptor;

wherein the transactivation domain is from a nuclear receptor other than an ecdysone receptor, a retinoid X receptor, or an ultraspiracle receptor, and wherein the first and second polypeptides dimerize and bind to a ligand;

II)

a) a first gene expression cassette comprising a tissue-specific promoter operably linked to a polynucleotide sequence that encodes a first polypeptide comprising:

a DNA-binding domain that recognizes a response element associated with a gene of interest; a ligand binding domain comprising at least a portion of a ligand binding domain from a truncated retinoid X receptor;

b) a second gene expression cassette comprising a tissue-specific promoter operably linked to a polynucleotide sequence that encodes a second polypeptide comprising:

a transactivation domain; and

a ligand binding domain comprising at least a portion of a ligand binding domain from a Group H nuclear receptor polypeptide;

wherein the transactivation domain is from a nuclear receptor other than an ecdysone receptor, a retinoid X receptor, or an ultraspiracle receptor, and wherein the first and second polypeptides dimerize and bind to a ligand.

34 . The inducible gene expression modulation system according to claim 33 , wherein each gene switch is associated with an expression cassette comprising:

a response element to which the DNA-binding domain of the first polypeptide binds;

a promoter that is activated by the transactivation domain of the second polypeptide; and a gene of interest.

35 . The inducible gene expression modulation system according to claim 33 , wherein the Group H nuclear receptor is an ecdysone receptor.

36 . The inducible gene expression modulation system according to claim 33 , wherein the tissue-specific promoters are developmentally-specific promoters.

37 . A vector comprising the inducible gene expression modulation system according to claim 33 .

38 . An isolated host cell into which the inducible gene expression modulation system according to claim 33 has been introduced.

39 . The isolated host cell according to claim 38 , wherein the host cell is selected from the group consisting of a bacterial cell, a fungal cell, a yeast cell, a plant cell, an animal cell, a mammalian cell, a mouse cell, and a human cell.

40 . A non-human organism comprising a host cell into which the inducible gene expression modulation system according to claim 33 has been introduced.