Transgenic mouse model for conditional fkbp51 expression and related methods

Abstract

The subject invention pertains to transgenic non-human animals comprising a transgenic nucleotide sequence, integrated into the genome of the animals, comprising a nucleotide sequence encoding human FKBP51 operably linked to a tetracycline response element. In some embodiments, the transgenic animal comprises an additional transgenic nucleotide sequence, integrated into the genome of the animal, comprising a nucleotide sequence encoding a tetracycline transactivator (tTA) operably linked to a promoter; wherein the tTA is expressed upon activation of the promoter and binds the tetracycline response element, thereby causing expression of FKBP51. The invention also pertains to methods for screening for agents for the prevention and/or treatment of psychiatric disorders, such as depression.

We claim: 
     
         1 . A transgenic non-human animal comprising:
 a transgenic nucleotide sequence, integrated into the genome of the animal, comprising a nucleotide sequence encoding human FKBP51 operably linked to a tetracycline response element.   
     
     
         2 . The transgenic animal of  claim 1 , wherein the transgenic nucleotide sequence is integrated into the genome at a specific chromosomal locus. 
     
     
         3 . The transgenic animal of  claim 2 , wherein the transgenic nucleotide sequence is integrated into the genome at a specific, non-disruptive chromosomal locus. 
     
     
         4 . The transgenic animal of  claim 1 , further comprising:
 an additional transgenic nucleotide sequence, integrated into the genome of the animal, comprising a nucleotide sequence encoding a tetracycline transactivator (tTA) operably linked to a promoter;   wherein the tTA is expressed upon activation of the promoter and binds the tetracycline response element, thereby causing expression of FKBP51.   
     
     
         5 . The transgenic animal of  claim 4 , wherein tTA is unable to bind the tetracycline response element in the presence of tetracycline, or a tetracycline derivative, thereby inhibiting expression of the nucleotide sequence encoding human FKBP5.1 
     
     
         6 . The transgenic animal of  claim 1 , wherein the animal is a mouse. 
     
     
         7 . The transgenic animal of  claim 4 , wherein the animal is a mouse. 
     
     
         8 . The transgenic animal of  claim 4 , wherein the promoter is selected from the group consisting of a constitutive promoter, a tissue-specific promoter, a development-stage-specific promoter, and an inducible promoter. 
     
     
         9 . The transgenic animal of  claim 4 , wherein the promoter is a tissue-specific promoter. 
     
     
         10 . The transgenic animal of  claim 9 , wherein the tissue-specific promoter is a brain specific promoter, wherein the tTA is expressed in the brain and binds the tetracycline response element, thereby causing expression of FKBP51 in the brain. 
     
     
         11 . The transgenic animal of  claim 9 , wherein the tissue-specific promoter is a Ca2+/calmodulin-dependent protein kinase II (CaMKIIa) promoter that is specific for the forebrain, wherein tTA is expressed in the forebrain and binds the tetracycline response element, thereby causing expression of FKBP51 in the forebrain. 
     
     
         12 . The transgenic animal of  claim 11 , wherein the transgenic animal exhibits depressive behavior. 
     
     
         13 . A method for screening therapeutic agents for the treatment of one or more psychiatric disorder, comprising:
 administering an agent to the transgenic animal of  claim 4 ;   determining the effect of the agent on one or more phenotype of the one or more psychiatric disorder; and   comparing the effect to an untreated control animal, wherein an improvement in any one or more of the phenotypes indicates the agent is a therapeutic agent.   
     
     
         14 . The method of  claim 13 , wherein the one or more psychiatric disorder is selected from the group consisting of post-traumatic stress disorder, bipolar disorder, depression and combinations thereof. 
     
     
         15 . A method for screening therapeutic agents for the treatment of depressive-like behavior, comprising:
 administering an agent to the transgenic animal of  claim 4 ;   determining the effect of the agent on one or more phenotype of the depressive-like behavior; and   comparing the effect to an untreated control animal, wherein an improvement in any one or more of the phenotypes indicates the agent is a therapeutic agent.   
     
     
         16 . A method for screening for an agent for the prevention or treatment of accumulation of FKBP51 in the forebrain, comprising:
 providing a potential therapeutic agent;   administering the potential therapeutic agent to the transgenic animal of  claim 4 ;   determining whether because of the administering of the potential therapeutic agent, accumulation of FKBP51 in the forebrain of the transgenic animal is prevented or slowed by comparison to a control animal not treated with the agent.   
     
     
         17 . A transgenic non-human animal comprising:
 a transgenic nucleotide sequence, integrated into the genome of the animal, comprising a nucleotide sequence encoding human FKBP51 operably linked to a tetracycline response element; and   an additional transgenic nucleotide sequence, integrated into the genome of the animal, comprising a nucleotide sequence encoding a tetracycline transactivator (tTA) operably linked to a promoter;   wherein the tTA is expressed upon activation of the promoter and binds the tetracycline response element, thereby causing expression of FKBP51.