Evaluation of the differential roles of Bone Morphogenetic Proteins during vascular development

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Bone Morphogenetic Proteins (BMPs) play crucial roles in the formation of the vascular system. Indeed, the BMP signalling pathway has important functions in endothelial differentiation, venous specification, and angiogenesis, during development. Of particular importance in vascular development is the BMP receptor Activin-like receptor Kinase 1 (Alk1), which is almost exclusively expressed by endothelial cells, and is a critical regulator of vascular remodeling. Alk1 loss-of-function results in defective vascular development, characterized by immature, dilated vessels prone to forming arteriovenous malformations (AVM). Other BMP receptors, Alk2 and Alk3, have also been shown to have important roles in vascular growth and permeability. Interestingly, the activity of BMP receptors appears to be context-dependent, as they can promote angiogenesis under certain conditions while preventing it in other contexts.***It is now clear that BMP signalling is under more complex and dynamic regulation than previously thought. To understand the functional details of BMP signalling more precisely, it is important to reveal when, where, and how it is dynamically propagated, for which the visualization of BMP signalling is essential. The goal of the present proposal is to evaluate how the signalling of BMPs is propagated in endothelial cells and the spatio-temporal activation pattern of BMP receptors during vascular development.***This research program will first evaluate the signalling of individual BMP receptors in the endothelium. Using genetic, proteomics and cell signalling approaches, we will identify the key signalling specificities of each type I BMP receptor (Alk1, Alk2, Alk3) in endothelial cells. The second part of the research program will involve investigating where and when each BMP receptor is activated at specific stages of vascular development. For this, we have generated a live reporter system to detect the activation of BMP receptors in real time.******The following research projects will be developed:***Aim 1: Evaluate the functional consequences of the signalling of individual BMP receptors (Alk1, Alk2 and Alk3) in endothelial cells***Aim 2: Generation and validation of BMP signalling reporters: Human and mouse versions of Alk1 and Alk3 reporters, which become fluorescent once activated, will be produced and validated.***Aim 3: Evaluate BMP receptor signalling in vivo: Transgenic mice expressing BMP signalling reporters will be generated. Spatiotemporal activation of the reporter constructs will be assessed during vascular development.***The knowledge generated by this research program will to produce a comprehensive model of how and when the signalling of BMPs is generated, regulated and accomplished during vascular development.