Transgenic animals for studying regulation of genes

Abstract

A transgenic non-human animal (e.g., a transgenic mouse) comprising a polynucleotide encoding a soluble marker protein functionally linked to a regulatory sequence of an endogenous gene encoding E-selectin. Also described are methods for detecting modulators of the E-selectin gene using said transgenic non-human animal, and cultured cells obtained therefrom.

What is claimed is:  
     
         1 . A transgenic or somatic recombinant non-human animal comprising a polynucleotide encoding a soluble marker protein functionally linked to a regulatory sequence of an endogenous gene encoding E-selectin.  
     
     
         2 . A transgenic or somatic recombinant non-human animal according to  claim 1  having the polynucleotide encoding a soluble marker protein inserted into a region of an E-selectin gene of a chromosomal E-selectin allele of said animal, which is between a transcription start site and a translation start site of said E-selectin gene.  
     
     
         3 . A transgenic or somatic recombinant non-human animal according to  claim 1  wherein the soluble marker protein is a secreted alkaline phosphatase.  
     
     
         4 . A transgenic or somatic recombinant non-human animal according to  claim 2  wherein the soluble marker protein is a secreted alkaline phosphatase.  
     
     
         5 . A transgenic or somatic recombinant non-human animal according to  claim 1  wherein the animal is a transgenic animal.  
     
     
         6 . A transgenic or somatic recombinant non-human animal according to  claim 1  wherein the animal is a transgenic mouse.  
     
     
         7 . A transgenic mouse having in its genome a soluble reporter transgene under the control of the promoter of an E-selectin gene of a chromosomal E-selectin allele.  
     
     
         8 . A transgenic mouse according to  claim 7  wherein the soluble marker protein is a secreted alkaline phosphatase.  
     
     
         9 . A transgenic knockout mouse which is homozyous or heterozygous for a chromosomal E-selectin allele comprising a genetic construct comprising a soluble reporter transgene, said soluble reporter transgene being under the control of the promoter of the E-selectin gene of said chromosomal E-selectin allele, and said genetic construct being inserted into a region which is between a transcription start site and a translation start site of the E-selectin gene of the chromosomal E-selectin allele.  
     
     
         10 . A transgenic mouse according to  claim 9  wherein the soluble marker protein is a secreted alkaline phosphatase.  
     
     
         11 . A transgenic mouse according to  claim 10  wherein the genetic construct comprises SEQ ID NO: 11 or SEQ ID NO: 12.  
     
     
         12 . An isolated cell derived from the transgenic mouse according to  claim 9 .  
     
     
         13 . DNA having SEQ ID NO: 9 or SEQ ID NO: 10.  
     
     
         14 . A method of screening for an agent having therapeutic utility, comprising 
 (a) administering the agent to a transgenic or somatic recombinant non-human animal according to  claim 1     (b) monitoring marker concentration in a body fluid of said animal, and    (c) comparing said marker concentration to the concentration of marker in an untreated transgenic or somatic recombinant non-human animal, an elevated level being indicative of the therapeutic utility of the agent.    
     
     
         15 . A method of screening for an agent which is a modulator of E-selectin expression, comprising: 
 (a) administering the agent to a transgenic or somatic recombinant non-human animal according to  claim 1 ,    (b) monitoring marker concentration in a body fluid, and    (c) comparing said marker concentration to the concentration of marker in an untreated transgenic or somatic recombinant non-human animal, an modulated level being indicative of the capability of said agent of modulating E-selectin expression.    
     
     
         16 . A novel modulator of E-selectin expression identified by a method according to  claim 15 .  
     
     
         17 . A method for treating a patient suffering from an inflammatory, thrombotic, ischaemic or neoplastic condition or from transplant rejection comprising administering to the patient a pharmaceutically effective amount of a modulator acording to  claim 16 .  
     
     
         18 . A method of monitoring disease progression comprising 
 (a) crossing a transgenic non-human animals according to  claim 1  with an animal strain used as an animal model,    (b) recovering at least one offspring, and    (c) monitoring at least one offspring for disease progression in relation to marker concentration in a body fluid.