Atherosclerosis and associated cardiovascular disease are the leading causes of mortality in developed countries and the World Health Organization has estimated that by 2020 these disorders will be the main sanitary and socio-economic problem world-wide due in part to the progressive aging of our societies. Atherosclerosis is a complex chronic inflammatory process triggered and perpetuated by cardiovascular risk factors which cause endothelial dysfunction and leukocyte infiltration within the subendothelial space in the artery wall. The most prominent immune cells that invade lesions are monocytes/macrophages (comprising up to 60% of atheromata mass) and T-lymphocytes. Recent evidences suggest that different atherosclerotic stages are associated with distinct macrophage subtypes, principally the classically-activated (M1) and alternatively-activated (M2) populations. The main obstacle to the anti-atherosclerotic therapy based on targeting atherosclerotic macrophage is that very little is known about the intracellular pathways and transcription factors involved in macrophage activation. I recently demonstrated that the transcription factor c-Myc is specifically induced in human macrophages during M2 alternative activation and controls the expression of around 50% of M2-specific markers. The main goal of this project is to elucidate the role thatc-Myc plays in macrophage functions that are relevant in atherosclerosis (eg., proliferation, apoptosis, migration, lipid uptake) and the effects of ablating macrophage c-Myc expression on disease initiation and progression.
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