Humanized transgenic animal

Abstract

This present invention relates to transgenic animals useful to study human diseases. Specifically, the invention relates to transgenic animals expressing at least two human proteins (optionally in replacement of the counterpart proteins in the animal) whereas a first human protein interacts with a second human protein. The transgenic animals can then be used for evaluating drugs or building disease models that are related to the expressed human proteins in the animals. The animals and methods disclosed herein reduce the possibility identifying a false-positive compound—the compound that show an effect in a naturally-occurring, non-transgenic animal but may not necessarily work or be therapeutic in human, since the compound may only interrupt the interaction between two animal proteins not necessarily two related human proteins. Also, the animals and methods disclosed herein reduce the possibility of identifying a false-negative compound—a compound that does not work or have any effect in a naturally-occurring, non-transgenic animal but may have therapeutic effect in human, since the compound may only interrupt the interaction between at least two relevant human proteins not necessarily two related animal proteins.

What is claimed is: 
     
         1 . A humanized transgenic animal comprising a first human gene encoding a first human protein and a second human gene encoding a second human protein, wherein the first human protein and the second human protein interacts with each other. 
     
     
         2 . The humanized transgenic animal of  claim 1  wherein a first animal gene substantially homologous to the first human gene in the transgenic animal genome is replaced by the first human gene. 
     
     
         3 . The humanized transgenic animal of  claim 1  wherein a first animal gene substantially homologous to the first human gene in the transgenic animal genome is replaced by the first human gene and a second animal gene substantially homologous to the second human gene in the transgenic animal genome is replaced by the second human gene. 
     
     
         4 . The humanized transgenic animal of  claim 1  wherein the transgenic animal is produced by introducing the first and second human genes into the genome of an embryonic stem cell which develops into the transgenic animal. 
     
     
         5 . The humanized transgenic animal of  claim 4  wherein the first animal gene substantially homologous to the first human gene in the transgenic animal genome is replaced by the first human gene. 
     
     
         6 . The humanized transgenic animal of  claim 4  wherein the first animal gene substantially homologous to the first human gene in the transgenic animal genome is replaced by the first human gene and a second animal gene substantially homologous to the second human gene in the transgenic animal genome is replaced by the second human gene. 
     
     
         7 . The transgenic animal in  claim 1  comprising mouse, rat, rabbit and non-human primate. 
     
     
         8 . The humanized transgenic animal of  claim 1  wherein the expression of the first human protein and the second human protein in the transgenic animal lead to a disease in the animal. 
     
     
         9 . A method of making a humanized transgenic animal of  claim 1  comprising the steps of introducing a first human gene and a second human gene into an embryonic stem cell which develops into the transgenic animal. 
     
     
         10 . The method of making a humanized transgenic animal of  claim 9  wherein a first animal gene substantially homologous to the first human gene in the transgenic animal genome is replaced by the first human gene and/or a second animal gene substantially homologous to the second human gene in the transgenic animal genome is replaced by the second human gene. 
     
     
         11 . A method of evaluating whether a molecule modulates human protein interaction in a animal comprising the steps of administering the molecule in a humanized transgenic animal of  claim 1  and determining whether the human protein interaction is modulated. 
     
     
         12 . A method of evaluating whether a molecule modulates a disease in a animal comprising the steps of administering the molecule in a humanized transgenic animal of  claim 1  and determining whether the disease is modulated. 
     
     
         13 . A method of making a humanized transgenic animal of  claim 1  comprising:
 knocking-in a first human gene to a first animal such that the first animal expresses a first human protein encoded by the first human gene; 
 knocking-in a second human gen to a second animal such that the second animal expresses a second human protein encoded by the second human gene; 
 breeding the first animal and the second animal to produce an off spring that expresses both fist human protein and the second human protein, 
 wherein the first human protein and the second human protein interacts with each other.