Project description DEENESFRITPL Finding the 'switches' to fine-tune macrophage phenotypes in inflammatory diseases The immune system has many soldiers to fight its battles against invaders. Among them are macrophages, a type of white blood cell that responds to an infection or to an accumulation of damaged or dead cells. As their name suggests, they are large cells that 'eat' their targets and can start an immune response when it 'sees' an infection. Inflammation is vital to the immune system's response to injury and infection, however, these properties can turn against the body in diseases such as atherosclerosis and sepsis. The EU-funded MacrophageEGR project is investigating two different transcriptional regulators whose activation by pro- or anti-inflammatory signals either enhances or represses macrophage activation. By targeting these transcriptional regulators, it may be possible to prevent macrophages from developing phenotypes favouring inflammatory diseases. Show the project objective Hide the project objective Objective Macrophages play important roles in many aspects of immunity and therefore contribute to a diverse range of human inflammatory diseases, including atherosclerosis. The expression of macrophage genes is tightly controlled by regulatory DNA elements, such as enhancers. When macrophages are exposed to external stimuli, specific transcription factors affect enhancer activity, thereby impacting macrophage function in health and disease.I am investigating macrophage enhancer activation by interleukin-4 (IL-4). IL-4 is an important anti-inflammatory cytokine that suppresses macrophage activation and regulates immune responses during parasitic infections and allergies. I discovered that IL-4 activates the transcription factor Egr2 leading to specific IL-4-induced enhancer activation in macrophages. I surprisingly noticed that Egr1, while binding highly similar DNA motifs as Egr2, actually represses enhancer activity when macrophages are exposed to pro-inflammatory stimuli, indicating antagonistic effects of Egr1 and Egr2. By targeting transcriptional regulators, macrophages can be skewed to disease-favorable phenotypes. I here propose to investigate and target Egr1 and Egr2 in pro- and anti-inflammatory macrophage phenotypes in vitro and in disease.Aim 1: To elucidate the molecular mechanism resulting in differential outputs of Egr1 and Egr2 binding, I will study the transcription factor complexes in which Egr1/Egr2 function.Aim 2: To characterize the function of Egr1 and Egr2 in macrophages, I will study the effects of Egr1/Egr2 deletion in mouse and human macrophages.Aim 3: To study the roles of Egr1 and Egr2 in macrophage-driven diseases, I will delete Egr1/Egr2 in macrophages and assess the effect of deletion on atherosclerosis and endotoxemia.My proposed studies will reveal the role of macrophage Egr1 and Egr2 in disease and contribute to increased knowledge on how disease-associated signals regulate enhancer activity in disease-relevant cell types. Fields of science medical and health scienceshealth sciencesinflammatory diseasesnatural sciencesbiological sciencesgeneticsDNAmedical and health sciencesclinical medicinecardiologycardiovascular diseasesarteriosclerosismedical and health sciencesbasic medicineimmunologymedical and health sciencesclinical medicineallergology Programme(s) H2020-EU.1.3. - EXCELLENT SCIENCE - Marie Skłodowska-Curie Actions Main Programme H2020-EU.1.3.2. - Nurturing excellence by means of cross-border and cross-sector mobility Topic(s) MSCA-IF-2019 - Individual Fellowships Call for proposal H2020-MSCA-IF-2019 See other projects for this call Funding Scheme MSCA-IF - Marie Skłodowska-Curie Individual Fellowships (IF) Coordinator ACADEMISCH MEDISCH CENTRUM BIJ DE UNIVERSITEIT VAN AMSTERDAM Net EU contribution € 175 572,48 Address Meibergdreef 15 1105AZ Amsterdam Netherlands See on map Region West-Nederland Noord-Holland Groot-Amsterdam Activity type Higher or Secondary Education Establishments Links Contact the organisation Opens in new window Website Opens in new window Participation in EU R&I programmes Opens in new window HORIZON collaboration network Opens in new window Other funding € 0,00
