COLLABORATIVE PROJECTS

Summary of the proposal : the purpose of this exchange is to learn the innovative cell culture methodology of different parts of aorta (ascending, arch, and descending) developed by the host group (Elisabeth Genot). Her laboratory is interested in the role of TGF-beta in the formation of podosomes in endothelial cells. My laboratory is interested in the trafficking of TGF-beta receptors, and associated signaling components, in vascular smooth muscle cells and fibroblasts in patients with Marfan syndrome. This is a rare connective tissue-associated genetic disorder caused by mutations in the fibrillin-1 gene. The mutated protein leads to a fragmentation of the elastin network of the tunica media as a result of excessive degradation by matrix metalloproteases. A second mechanism by which the fibrillin mutation causes aortic disease in Marfan syndrome involves TGF-beta. There is evidence that mutant fibrillin 1 has a low affinity binding site for latent TGF-beta (its inactive form) and sequesters the cytokine (making it unaccessible for cells). In its absence and with the action of metalloproteases, levels of active TGF-beta rise and this leads to an aberrant cellular behaviour (of different kinds) amongst which an unusual configuration of the actin cytoskeleton. The main final clinical consequence of hyper-TGF-beta activity is the formation of aneurysm and rupture of the ascending aorta. Therefore, Marfan syndrome is an excellent translational medicine model for the study aneurysms, which result from alterations in the TGFbeta-associated signaling and the disassembly of the extracellular matrix. There is an animal model of this disorder (Marfan mice), which was generated by the laboratory of Hal Dietz (Baltimore, USA). This model is currently available in the laboratory of Dr Genot. The initial work plan is to visit the her laboratory and to learn to apply in my research her innovative method to culture endothelial cells from explants of different parts of aorta from Marfan mice.

Dr. Elisabeth Génot and myself had the opportunity to meet for a first time in a recent meeting hold in Madrid (Sept. 18-21 September; Podosomes, Invadopodia and Focal Adhesions in Physiology and Pathology) and we realized of our common interest in Marfan disease and of our complementarity aims in research.