Sustained injury of the myocardium can lead ultimately to heart failure. The restricted ability of the heart to repair after injury is due to inherent limited regenerative capacity of the bi-nucleated adult cardiomyocyte. A long sought goal has therefore been to identify approaches that facilitate cardiomyocyte proliferation and regeneration. CDKN1A interacting zinc finger protein 1 (CIZ1) is an alternatively spliced gene that has been shown to play a role in mammalian DNA replication in vitro. Full length CIZ1 protein localises to dynamic sub-nuclear foci, with co-localisation experiments suggesting significant association with DNA replication factories and active DNA synthesis. CIZ1 interacts directly with key regulators of the cell cycle, including Cdk2, cyclin E, cyclin A, and Cdk2 inhibitor p21. CIZ1 (and many of its splice variants) have been linked to a number of proliferative disorders, ranging from rheumatoid arthritis to cancer. In addition to actively proliferating cells, CIZ1 foci can be detected in terminally differentiated cells including adult cardiomyocytes. However, expression of new Ciz1 product at the mRNA level is very low in these cells, compared to non-myocyte cells of the heart. It is currently unclear whether the remaining protein retains function or is a remnant of the final round of cardiomyocyte DNA replication leading to the quiescent bi-nucleated state. This study aimed to investigate whether CIZ1 is a suitable candidate molecule for stimulating cardiomyocyte regeneration to aid restoration of normal heart function through re-establishment of cardiomyocyte self- renewal capacity. A conditional transgenic mouse model, in which CIZ1 is over- expressed specifically in cardiomyocytes has been generated. Transgenic hearts are enlarged due to cardiomyocyte hyperplasia, although Millar catheter assessment showed no evidence of cardiac dysfunction. Individual cardiomyocytes isolated from transgenic hearts exhibit altered nuclear dynamics, with a significant increase in the number of mono-nucleated cells relative to bi-nucleated. Furthermore, preliminary data using in vivo EdU DNA replication assays showed evidence of cell cycle reactivation in the transgenic hearts. Up-regulation of genes involved in G1 and G1/S phase transition has also been indicated. The results suggest that CIZ1 may be a suitable novel candidate for therapeutic application in cardiac regeneration following injury.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:589403 |
| Date | January 2012 |
| Creators | Bageghni, Sumia Abdulaziz |
| Publisher | University of Leeds |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
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