Objective The Wilms tumour suppressor, Wt1 is a transcription factor of the zinc-finger type. Evidence supports the hypothesis that Wt1 is important for Epithelial Mesenchymal Transition (EMT) in epicardial cells during cardiac development. Wt1 may be playing a key role in maintaining the balance of proliferation versus differentiation of cardiac vascular progenitor cells derived from the epicardium. Further evidence implicates Wt1 in the vascular regenerative response to myocardial ischaemia.The proposed project explores these hypotheses and attempts to dissect the mechanisms involved. In order to test the hypotheses about Wt1 function in this pathway we will inactivate Wt1 at different stages during the progression from proepicardium, to epicardium to Epicardial derived cells (EPDCs), to vascular tissue. I will make the appropriate crosses to produce mice that carry a floxed Wt1 allele opposite the Wt1 GFP allele and also carrying the tamoxifen-inducible Cre. Thus it should be possible to examine the influence of Wt1 disruption on the development of the principal known Wt1 targets in cardiovascular system.In addition, I will determine whether they may be contributing to the observed cardiac defect observed in the Wt1 null mice. Culturing epicardial explants from these mice I will directly demonstrate the importance of this factor in the EMT transformation during heart formation. I will also identify the molecular mechanism of Wt1 induced EMT and maintaining of cardiac vascular progenitor cells. Using chromatin immunoprecipitation I will investigate the hypothesis that Wt1 activates the Snail gene and that defects in the EMT and EPDCs proliferation may result from reduced Snail production in the Wt1 null mice. In addition, I will also analyse if over-expression of Sn ail in epicardial cells could revert the Wt1 null phenotype. Finally, using the conditional Wt1 line I will be able to test whether Wt1 function is important for the vascular repair response to ischaemia Fields of science medical and health sciencesmedical biotechnologycells technologiesstem cellsmedical and health sciencesclinical medicineoncology Keywords Wilms' tumour suppressor gene Wt1 coronary vessels epicardium epithelial to mesenchymal transition myocardial ischaemia Programme(s) FP6-MOBILITY - Human resources and Mobility in the specific programme for research, technological development and demonstration "Structuring the European Research Area" under the Sixth Framework Programme 2002-2006 Topic(s) MOBILITY-2.1 - Marie Curie Intra-European Fellowships (EIF) Call for proposal FP6-2005-MOBILITY-5 See other projects for this call Funding Scheme EIF - Marie Curie actions-Intra-European Fellowships Coordinator MEDICAL RESEARCH COUNCIL Address 20 park crescent London United Kingdom See on map Links Website Opens in new window EU contribution € 0,00
