NUCLEAR RECEPTORS · Modulation of genetic programs of macrophages in atherogenesis
FP6 — Marie Curie Actions (Human Resources and Mobility)
- Duration
- 2005-10-01 → 2007-09-30
- EU contribution
- €80,000
- Participants
- 1
- Scheme
- IRG
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Results in brief
Final Activity Report Summary - NUCLEAR RECEPTORS (Modulation of genetic programs of macrophages in atherogenesis)
The leading cause of death in Europe and the cause of more than half of all mortality in the world developed countries is atherosclerosis and has long been a disease that has puzzled scientist and physicians. Atherosclerotic coronary heart disease is the underlying cause for most heart attacks, and one of the most common causes for congestive heart failure, cardiac arrhythmia, and sudden death due to heart attack. To cure atherosclerosis, we must understand its molecular biology. Knowing the molecular components will provide us a potential way for drug development and pharmacological intervention. Macrophages, immune system scavengers, guard against disease by ingesting particulate material, including microbes. Macrophages play a key role in atherosclerosis because, under the right conditions, take up oxidized low-density lipoproteins (LDL), which is often referred to as bad cholesterol and become a foam cell. The observation that the PPAR-gamma receptor (Peroxisome Proliferator Activated Receptor) and its obligatory partner the Retinoid X Receptor (RXR) are highly expressed in macrophage foam cells within coronary lesions raising many questions about their potential functions in cardiovascular disease. This issue is especially relevant given the frequency of cardiovascular complications in subjects with type 2 diabetes, an obesity related disease and the single largest risk factor for heart disease, which now have the option to be treated with drugs that regulate PPAR-gamma activity. Our studies have led important insights into the regulation of inflammatory factors in macrophages, the role of PPAR/RXR in atherogenesis and diabetes type 2, and the potential use of PPAR/RXR ligands for therapeutic purposes.
Data: CORDIS, © European Union
Project 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.
Original text from CORDIS.
Participants
- FUNDACIÓN CENTRO NACIONAL DE INVESTIGACIONES CARDIOVASCULARES CARLOS III · MADRIDCoordinatorCity levelSpain
Links
Data: CORDIS, © European Union