Compositions and method for manipulating pim-1 activity in circulatory system cells

Abstract

The invention provides compositions (e.g., pharmaceutical compositions) comprising nucleic acids encoding the serine/threonine kinase PIM-1, and methods for making and using them; including methods for inducing cellular proliferation, and protecting cardiac cells from hypoxia and cellular apoptosis. The invention provides compositions (e.g., pharmaceutical compositions) comprising nucleic acids encoding PIM-1, and methods for enhancing the regenerative potential of stem cells in the heart.

1 . A method, comprising identifying a patient in need of enhanced PIM activity in a vascular system cell or tissue, and enhancing levels of PIM in the vascular system cell or tissue of the patient to alter a functional characteristic of cells in that tissue. 
     
     
         2 . The method of  claim 1 , wherein:
 (a) the patient has experienced cardiac injury and the enhanced PIM levels facilitate cardiac regeneration to repair that injury; and   (b)   the enhancing step comprises administering cells to the patient that produce enhanced levels of PIM.   
     
     
         3 - 5 . (canceled) 
     
     
         6 . A composition, comprising a vascular system cell or a cell can differentiate into a vascular system cell, wherein the cell comprises a PIM-encoding polynucleotide sequence operably linked to a non-PIM promoter. 
     
     
         7 . The composition of  claim 6 , wherein:
 the cell is a stem cell or cardiac progenitor cell that can differentiate into a heart cell.   
     
     
         8 . (canceled) 
     
     
         9 . The method of  claim 2 , wherein the cardiac disease or injury comprises: ischemic injury, hypoxic injury, myocardial infarction, traumatic cardiac injury, cardiac hypertrophy, overpressure injury, congestive heart failure, apoptosis-inducing injury or disease, bacterial infection, viral infection. 
     
     
         10 . A pharmaceutical composition formulated for administration to a heart muscle comprising:
 a Pim-1 encoding nucleic acid operably linked to a promoter and inserted in a viral vector.   
     
     
         11 - 12 . (canceled) 
     
     
         13 . A method for inducing expression of a PIM-1 nucleic acid in a cardiac or vascular cell or tissue ex vivo, comprising:
 (a) providing a Pim-1 encoding nucleic acid; and inserting the Pim-1 encoding nucleic acid into the cardiac or vascular cell or tissue; (ii) providing a cell expressing and/or secreting a Pim-1 kinase; (iii) administering Pim-1 kinase or a Pim-1 expressing nucleic acid to the cardiac or vascular cell, tissue or organ; or, (iv) providing a compound that induces or upregulates PIM-1 nucleic acid or a Pim-1 kinase activity in a cardiac or vascular cell, tissue or organ; and   (b)   implanting the cardiac or vascular cell or tissue into an individual in need thereof.   
     
     
         14 . (canceled) 
     
     
         15 . The method of  claim 2 , wherein the cardiac injury comprises a cellular apoptosis, a hypoxia, a hypoxaemia, an anoxia, an infarction, a trauma, a surgery, a reimplantation, a transplantation or is caused by a toxin, or by an inflammation, an infection, a chronic stress, a diabetes, an alcoholism; or an oxidative damage. 
     
     
         16 - 17 . (canceled) 
     
     
         18 . The method of  claim 1 , wherein the method further comprises enhancing the expression of a bcl-2, a bcl-XL and/or phosphorylation of a Bad protein in a cardiac or vascular cell, tissue or organ. 
     
     
         19 . The method of  claim 1 , wherein the method is effective for the amelioration, treatment or prevention of ischemia reperfusion injury in a cardiac or vascular cell, tissue or organ. 
     
     
         20 . The method of  claim 1 , further
 comprising overexpressing or expressing Pim-1 in a stem cell or a pluripotent cell to enhance the regenerative potential of the stem cell or pluripotent cell.   
     
     
         21 . The method of  claim 2 , wherein the cell is a stem cell, an adult stem cell, a hematopoietic stem cell, an adipose-derived stem cell, a mesenchymal stem cell, a c-kit +  stem cell, a human stem cell, an autologous or allogeneic stem cell, an embryonic cell, a tissue-specific resident stem cell, an allogeneic or autologous cell, a progenitor cell, a placental and/or cord blood cell, a Sca-1+ cell, or a CD34+ cell.