The aim of the present project is to analyze gene expression in normal human fibroblasts stimulated with platelet-derived growth factors (PDGFs) using the DNA micro array technology. The target genes will be connected with signaling cascades and PDGF activities. Preliminary experiments indicate that PDGF regulates a group of genes involved in cholesterol metabolism. This observation, which was confirmed by RT-PCR, suggests that PDGF might stimulate membrane synthesis and modify its composition and fluidity. Our data also suggest that the SREBP transcription factor is responsible for this effect. Using a dominant negative variant of this factor, we will assess the role of cholesterol synthesis stimulation by PDGF for fibroblast proliferation and migration. The importance of SREBP activation by PDGF in tumor cells, which have an altered lipid metabolism, will be investigated in vitro and in vivo. Cholesterol metabolism regulation by PDGF could also contribute to atherosclerosis, a process in which PDGF is known to play a important role. We will test this hypothesis using apolipoprotein E-deficient mice, a well characterized model for this disease. We hope to identify other interesting groups of genes relevant to PDGF activities. In summary , this project will focus on a new aspect of PDGF function and could have some consequences on the understanding and the treatment of diseases that involve PDGF.