Nucleic Acid Construct Comprising a P16 Promoter Controlling Expression of a Transgene that Causes Apoptosis in Senescent Cells

Abstract

This document relates to methods and materials involved in the removal of senescent cells within a mammal. For example, transgenic non-human animals that can be induced to delete senescent cells are provided.

What is claimed is: 
     
         1 . A nucleic acid construct comprising a p16 Ink4a  promoter sequence operably linked to a nucleic acid sequence encoding a polypeptide such that the polypeptide is selectively expressed when the construct is present in senescent cells,
 wherein expression of the polypeptide directly induces cell death in senescent cells but in less than 10% of non-senescent cells, thereby delaying presentation or progression of an age-related phenotype in or around a location where the senescent cells are present in vivo.   
     
     
         2 . The nucleic acid construct of  claim 1 , wherein the polypeptide comprises a caspase polypeptide sequence. 
     
     
         3 . The nucleic acid construct of  claim 1 , wherein said polypeptide comprises an FKBP sequence 
     
     
         4 . The nucleic acid construct of  claim 1 , wherein said polypeptide is an FKBP-caspase 8 fusion polypeptide. 
     
     
         5 . The nucleic acid construct of  claim 1 , further comprising an internal ribosome entry site (IRES) sequence followed by a nucleic acid sequence encoding a marker polypeptide 
     
     
         6 . A host cell containing a nucleic acid construct according to  claim 1 . 
     
     
         7 . The host cell of  claim 6 , which is a fertilized ovum. 
     
     
         8 . A host cell containing a nucleic acid construct according to  claim 2 . 
     
     
         9 . The host cell of  claim 8 , which is a fertilized ovum. 
     
     
         10 . A method of genetically altering a host cell, comprising transfecting the host cell with a nucleic acid construct according to  claim 1 . 
     
     
         11 . A method of producing a transgenic mouse, comprising providing a fertilized ovum containing a nucleic acid construct according to  claim 1 , and producing a founder line of transgenic mice from the fertilized ovum such that the transgenic mice have the nucleic acid construct in their genome. 
     
     
         12 . A transgenic mouse comprising a nucleic acid construct according to  claim 3  in its genome;
 wherein polypeptide directly induces cell death in senescent cells in the mouse and induces cell death in less than 10% of non-senescent cells in the mouse; 
 whereby presentation or progression of an age-related phenotype is delayed in the mouse as a result of expression of the polypeptide in the senescent cells.