SOX18-VEGF cross-regulation during angiogenesis and blood vascular development (2016–2017)

Abstract:
Development of the blood vascular tree is essential for embryonic development and foetal implantation. This biological process also plays a pivotal role under pathological conditions such as tumorogenesis, peripheral vascular disorders (eye disease, stroke), or tissue regeneration (neo-angiogenesis). The focus of this application is to delineate at a molecular level how the combination of vascular endothelial growth factors (VEGF) and transcription factor (SOX18) activities modulate gene expression to control the formation of the blood vascular network. These molecular events are likely to be recapitulated in disease-stimulated angiogenesis such as eye disorders or ocular injury. We have recently identified a novel mechanism of cross-talk between Sox18 and Vegfd (CIA and CIB Duong et al. Blood 2014) and Sox18 and Vegfc (CIA and CIB Cermenatti et al ATVB 2013) in knockout mouse and zebrafish models that lead to dramatic defects in embryonic blood and lymphatic vascular development. Here we test the hypothesis that feedback loops between VEGF receptor signalling pathways and SOX18-regulated transcription control angiogenesis and the formation of vascular networks. Specific aims are: 1) To investigate the biochemical mechanisms by which VEGFs modulates SOX18 transcriptional activity. 2) To assess how SOX18 modulates the response to VEGF signalling pathway. 3) To assess Sox18/VEGF¿¿¿s interplay in eye disease. Significance: This project will advance our knowledge of disease mechanisms and investigates the molecular driver of vascular disorder associated with eye disease This research proposal will produce important new knowledge about how growth factors and transcription factors co-operate in feedback loops to modulate a developmental process such as angiogenesis This research will open up therapeutic avenues for modulating neo-angiogenesis in the context of...
Grant type:
Cancer Council Queensland
Funded by:
Cancer Council Queensland