Analysis of the GTPase Rac1 in the arterial system and its implication in the hypertension – GRacArt

Arterial diseases have engendered growing interest do their unfavorable impact on cardiovascular morbidity and mortality. Arterial hypertension is a common health problem that affects 25% of the adult population in industrialized societies and a major risk factor of myocardial infarction and stroke. Hypertension is associated with a number of physiological and biochemical changes in the vessel wall, characterized by excessive contraction, growth and proliferation of smooth muscle cells. Mechanisms and signaling pathways that are involved in these structural and functional vessel wall changes are the subject of intensive research because they may permit identification of potential therapeutic targets for the development of novel pharmacological strategies. However, the pathogenesis of hypertension, as well as the basic mechanisms of blood pressure control, are still insufficiently understood. The aim of my project is to identify the molecular mechanisms involved in the pathogenesis of vascular diseases and to identify new therapeutic targets. Rho proteins (RhoA, Rac1') are major regulators of essential vascular smooth muscle cell functions. Increasing evidence has accumulated to implicate over-activation of Rho proteins as a common component for the pathogenesis of several cardiovascular disorders including hypertension. Recently, genetic analyses revealed that Rac1 could be involved in human arterial pathologies. However, the role of Rac1 in vivo and in the cardiovascular system is still poorly understood. By using both experimental models and developing approaches in human, the specific aim of my project is to determine the role of Rac1 in the cardiovascular system and to establish its involvement in hypertension. Specifically, the main objectives that I would like to carry out are: (a) To perform signaling and gain/loss-of function studies investigate the role of Rac1 GTPase in vitro in the vascular smooth muscle and endothelial cells and to identify its regulators in each type of cell. (b) To dissect genetically, through the use of genetically modified mouse strains, the role of Rac proteins and Rac-dependent routes in the normal function and physiology of the cardiovascular system and its pathological alterations. (c) To conduct genomic and proteomic approaches to determine if GTPase proteins and their regulators could be new biological markers of hypertension in human. These studies will allow us to demonstrate the role of Rac1 protein in cardiovascular processes and diseases. Furthermore, I hope that the consecution of these research aims will make it possible the identification of new diagnostic and prognostic factors for cardiovascular disease and the development of new drug targets with which to treat hypertension and may be diverse other cardiovascular dysfunctions. This project will be developp in the Institute of the thorax. This cardiovascular research is identified as one of the excellent areas of research in Nantes. The objective of my installation and the development of my team in this structure is to bring new skills and my expertise in vascular physiopathology and to strengthen this area of research.