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BRAVE Report Summary

Project ID: 309792
Funded under: FP7-IDEAS-ERC
Country: Belgium

Final Report Summary - BRAVE (Bicuspid Related Aortopathy, a Vibrant Exploration)

Research and technological achievements
The general purpose of this project was to find predictors of outcome of bicuspid aortic valve associated aortopathy (BAV/TAA) and to elucidate the etiologies and pathogenic mechanisms leading to aneurysm formation. In the first objective, we aimed at identifying genetic alterations causing BAV-associated TAA. Three different approaches are used: (1) gene prioritization (for which also new bioinformatic tool, called pBrit was developed) based on known BAV-genes, (2) burden analysis based on deleterious nature of variants, (3) burden analysis of incidence: unique or rare variants compared to control exomes and control databases. These analysis resulted in several new BAV/TAA genes, including KLF15, SEMA3C, ROBO4 and SMAD6. The genes revealed new pathways, especially those for guidance molecules for vascular patterning and endothelial to mesenchymal transition A further objective aimed at studying the role of the TGFbeta signaling in BAV/TAA. We studied the role of TGFB2, TGFB3, BGN and SMAD6 extensively and contributed several new insights to the pathogenesis of BAV/TAA. In the last objective, we aimed at developing at least one new mouse model for the study of BAV/TAA and we managed to deliver two models: KLF15 and SMAD6. The latter is currently still under detailed analysis and will offer an excellent platform for future strategies to develop new treatment strategies. In addition we also developed two new zebrafish models: sema3C and robo4.

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