Transgenic mouse model for conditional FKBP51 expression and related methods

Patent metadata

Field	Value
Publication number	US-10814015-B2
Application number	US-201715602985-A
Country	US
Kind code	B2
Filing date	May 23, 2017
Priority date	May 13, 2014
Publication date	Oct 27, 2020
Grant date	Oct 27, 2020

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.

First claim

We claim:

1. A method for screening for an agent for the prevention or treatment of accumulation of FKBP51 in the forebrain of a transgenic non-human mammal, comprising:
providing a potential therapeutic agent;
administering the potential therapeutic agent to a test transgenic non-human mammal, wherein the transgenic non-human mammal is chosen from a mouse, a rat, a goat, a sheep, and a pig;
determining the level of FKBP51 in the forebrain of the test transgenic non-human mammal;
identifying an agent as an agent for prevention or treatment of accumulation of FKBP51 in the forebrain when upon administering the potential therapeutic agent, the level of FKBP51 is reduced in the forebrain of the test transgenic non-human mammal compared to a control transgenic non-human mammal, wherein the control transgenic non-human mammal has the same genotype as that of the test transgenic non-human mammal and the potential therapeutic agent is not administered to the control transgenic non-human mammal;
wherein each of the test and the control transgenic non-human mammals comprises integrated into its genome:
i) a transgenic construct comprising a nucleotide sequence encoding a human FKBP51 operably linked to a tetracycline response element, and
ii) a transgenic construct comprising a nucleotide sequence encoding a tetracycline transactivator (tTA) operably linked to a brain-specific promoter, wherein the tTA is expressed in cells of the forebrain of said test and the control transgenic non-human mammals,
and wherein said tTA binds to the tetracycline response elements thereby causing expression in the forebrains of the test and the control transgenic non-human mammals of the human FKBP51.

2. The method according to claim 1 , wherein the brain specific promoter is an inducible promoter.

3. The method according to claim 2 , wherein the brain-specific promoter is a Ca 2+ /calmodulin-dependent protein kinase II (CaMKIIa) promoter that is specific for the fore brain, wherein tTA is expressed in the forebrains and binds the tetracycline response elements, thereby causing expression of FKBP51 in the forebrains of the test and control non-human animals.

4. The method according to claim 3 , wherein each of the test and control transgenic non-human animals is a mouse.

Assignees

• Univ South Florida

Inventors

• Dickey Chad
• Zhang Bo
• Blair Laura Jenelle

Classifications

• A01K2267/01

  Animal expressing industrially exogenous proteins · CPC title

• A01K2227/105

  Murine · CPC title

• C12N9/90

  Isomerases (5.) · CPC title

• A01K2267/0356

  Animal model for processes and diseases of the central nervous system, e.g. stress, learning, schizophrenia, pain, epilepsy · CPC title

• C12N15/8509

  for producing genetically modified animals, e.g. transgenic · CPC title