Objective Macrophages play a central role in atherogenesis. In addition to being transformed into foam cells, they secrete cytokines, growth factors and enzymes that affect function of other vascular cells thereby modulating the atherogenic process. However, little is known about the molecular events that regulate these processes in macrophages. Transcription factors that regulate cholesterol homeostasis and/or inflammatory responses represent potential therapeutic targets for patients with cardiovascular disease. The Retinoid X Receptor (RXR) is a nuclear receptor that plays an important role as a heterodimeric partner for the Peroxisome Proliferator Activated Receptors (PPARs) and the Liver X Receptors (LXRs). However, its ligand-activated role in vivo remains uncertain. We have recently obtained evidence that activated macrophages express RXRalpha, and that RXR ligands inhibit the transcription of genes that are upregulated during macrophage activation.This suggests that RXR plays a role in the regulation of chroni c inflammatory processes such as atherosclerosis. Studies proposed in this grant are aimed at identifying the functional role of RXRalpha in macrophage gene regulation, inflammation and atherogenesis. We propose the following Specific Aims: 1. To test the hypothesis that in vivo RXRalpha is critical for PPAR and LXR-mediated pathways in the macrophage. Macrophage specific disruption of the RXR gene will be achieved using the Cre-loxP approach. 2. We propose that RXRalpha may alter the development of athero genesis. This hypothesis will be tested by transplanting RXRalpha null bone marrow into LDL receptor knockout mice.These studies will provide new insights into the molecular mechanisms by which RXR modulates gene expression in atherosclerosis, and will support the potential use of RXR ligands for therapeutic purposes. This grant will give me the opportunity of returning to Europe providing the potential for me to become a leading European researcher. Fields of science medical and health sciencesbasic medicinepharmacology and pharmacydrug discoverymedical and health sciencesclinical medicinecardiologycardiovascular diseasescardiac arrhythmiamedical and health sciencesclinical medicinecardiologycardiovascular diseasesarteriosclerosismedical and health sciencesclinical medicineendocrinologydiabetesmedical and health sciencesbasic medicineimmunology Programme(s) FP6-MOBILITY - Human resources and Mobility in the specific programme for research, technological development and demonstration "Structuring the European Research Area" under the Sixth Framework Programme 2002-2006 Topic(s) MOBILITY-4.2 - Marie Curie International Reintegration Grants (IRG) Call for proposal FP6-2002-MOBILITY-12 See other projects for this call Funding Scheme IRG - Marie Curie actions-International re-integration grants Coordinator FUNDACIÓN CENTRO NACIONAL DE INVESTIGACIONES CARDIOVASCULARES CARLOS III EU contribution No data Address Sinesio Delgado, 4 MADRID Spain See on map Links Website Opens in new window Total cost No data
