WT1 CARDIOVASCULAR · Role of Wt1 in cardiovascular development in embryonic and adult life
6РП — Действия „Мария Кюри“
- Период
- 2007-01-01 → 2008-12-31
- Финансиране от ЕС
- 229 326 €
- Участници
- 1
- Схема
- EIF
Линиите свързват координатора с партньорите.
Накратко на български
Генът Wt1 регулира превръщането на клетки от външния слой на сърцето в кръвоносни съдове. Разбирането на този механизъм помага при изясняването на причините за сърдечните заболявания и развитието на клетъчни терапии.
Кратко обяснение, генерирано от езиков модел по текста на CORDIS. Оригиналът е по-долу.
Резултати накратко
Final Activity Report Summary - Wt1 cardiovascular (Role of Wt1 in cardiovascular development in embryonic and adult life)
Wilms tumour 1 (Wt1) is a gene originally identified as having been mutated in 10 to 15 % of the cases of the childhood kidney cancer called Wilms tumour. Mice which lack Wt1 die before birth. They have no kidneys, gonads or spleen and are thought to die from heart defects. Wt1 is present in the epicardium, which is the outermost layer of the heart. However, the function of Wt1 in the epicardium and in heart development is unknown. During heart development, the cells of the epicardium undergo a process, called epithelial to mesenchymal transition (EMT), which allows them to leave the sheet-like structure of the epicardium and become more mobile. These cells then undergo a differentiation process to become involved in making up the blood vessel that supplies the heart. I found that an epicardial-specific deletion of Wt1 led to a reduction in mesenchymal progenitor cells and their derivatives, including coronary smooth muscle and endothelial cells. I demonstrated that Wt1 was essential for EMT in cultured epicardial cells through direct transcriptional activation of Snail-1 and repression of E-cadherin, two of the major mediators of EMT. I also found that Wt1-deficient embryonic stem cells (ES) were unable to form mesodermal precursor cells during differentiation, and that this could be bypassed by reintroducing Snail-1 into these cells. The latter confirmed the importance of EMT, Wt1 and Snail-1 in the generation of differentiated cells. These new insights into the molecular mechanisms regulating cardiovascular progenitor cells and EMT were anticipated to shed light on the pathogenesis of heart diseases and could potentially help the development of cell-based therapies.
Текст от CORDIS, на английски · Данни: CORDIS, © Европейски съюз
Цел на проекта
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
Оригинален текст от CORDIS (на английски).
Участници
- MEDICAL RESEARCH COUNCIL · LONDONКоординаторОбединеното кралство
Връзки
Данни: CORDIS, © Европейски съюз