A novel marker for cardiomyocytes dedifferentiation
AssigneeNational University of Singapore
InventorsYike ZHU, Roger SY FOO
Life of this patent
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Abstract
The present invention relates to the Asparagine Synthetase (Asns) gene and the role it plays in cardiomyocyte dedifferentiation and cardiac regeneration. More particularly, the invention is directed to the detection of ASNS expression as a diagnostic marker for cardiomyocyte dedifferentiation and cardiac regeneration; therapeutic up- and downregulation of ASNS expression to augment dedifferentiation-regeneration or suppress dedifferentiation-regeneration; and methods of screening for ASNS inhibitors, activators and regulators of cardiomyocyte dedifferentiation activity. Also disclosed are vectors, probes, therapeutics and kits.
Claims23
A method of detecting cardiomyocyte dedifferentiation (CMDD) in a test sample from a subject, comprising:
- (a) determining an expression level of an Asparagine Synthetase (Asns) gene, protein or mRNA in the test sample;
- (b) comparing the expression level of the Asns gene, protein or mRNA in the test sample to that in a reference sample,
- wherein a difference in the level of the Asns gene, protein or mRNA in the test sample compared to the reference sample indicates that the test sample contains dedifferentiating cardiomyocytes.
A method of augmenting or suppressing cardiomyocyte dedifferentiation (CMDD), comprising:
- (a) contacting a cardiomyocyte with an expression vector comprising a polynucleotide sequence which increases the expression or activity of Asns, wherein the increase in expression or activity of Asns augments CMDD;
- or
- (b) contacting a cardiomyocyte with an expression vector comprising a polynucleotide sequence which suppresses the expression or activity of Asns, wherein the decrease in expression or activity of Asns suppresses CMDD.
(canceled)
-24. (canceled)
A method of screening for a therapeutic or prophylactic drug having cardiomyocyte dedifferentiation-promoting activity, comprising:
- (a) contacting a candidate therapeutic or prophylactic drug with cardiomyocytes or HEK293T cells;
- (b) detecting the expression level of Asns protein, mRNA, or Asns gene in the presence of the candidate drug;
- and
- (c) Identifying the candidate therapeutic or prophylactic drug as having cardiomyocyte dedifferentiation- or proliferation-promoting activity if the expression level of the Asns protein, mRNA or Asns gene increases compared to that of control cardiomyocytes or HEK293T cells unexposed to the candidate therapeutic or prophylactic drug.
A method of treatment of heart failure, comprising administering to a subject in need of such treatment a combination of an efficacious amount of:
- a) an expression vector comprising a polynucleotide sequence encoding Asns, and
- b) (i) an inhibitor of Hippo-Yap signalling or
- (ii) an activator of the ErbB2 pathway, or
- (iii) an upregulator of the expression of OSKM factors Oct4, Sox2, Klf4 and Myc, wherein the method promotes regeneration of heart tissue greater than that induced in the absence of the Asns expression vector.
-38. (canceled)
Dependencies are inferred from the claim text.