H2020Индивидуална стипендия2021–2023

MacrophageEGR · Egr1 and Egr2 regulate opposite transcriptional programs in macrophages

„Хоризонт 2020“ — Действия „Мария Склодовска-Кюри“

Период: 2021-09-01 → 2023-08-31
Финансиране от ЕС: 175 572 €
Участници: 1
Схема: MSCA-IF

Линиите свързват координатора с партньорите.

Накратко на български

Протеините EGR1 и EGR2 в имунните макрофаги регулират различни групи гени, свързани с възпаленията. Разбирането на тези механизми помага при разработването на терапии за автоимунни заболявания, инфекции и сърдечно-съдови проблеми.

Този кратък обзор е генериран от изкуствен интелект

Кратко обяснение, генерирано от езиков модел по текста на CORDIS. Оригиналът е по-долу.

Резултати накратко

Egr1 and Egr2 regulate opposite transcriptional programs in macrophages

My research aims to understand why two similar proteins, EGR1 and EGR2, have different effects on the activation of genes related to inflammation. Specifically, it investigates the molecular mechanisms behind these differences in gene activation. Understanding how these proteins regulate inflammation-related genes can have significant implications for the development of therapies for various diseases associated with inflammation, such as autoimmune disorders, infections, and cardiovascular diseases. By gaining insights into the molecular processes, researchers can potentially identify new targets for drug development and improve our understanding of the immune system. Objectives: 1: Investigate the differences between EGR1 and EGR2 in their ability to activate genes related to inflammation. This includes studying the timing of their activity and their interactions with other proteins in different strains of cells. 2: Examine the effects of removing or reducing EGR1 and EGR2 in macrophages (a type of immune cell) on gene activation and cell behavior. This helps confirm the findings from Objective 1 and provides insights into how these proteins influence cell phenotype. 3: Study the role of EGR2 in real-life disease models, specifically in the context of parasitic infections and atherosclerosis. This objective aims to understand how EGR2 affects disease outcomes in living organisms, providing valuable insights into its potential as a therapeutic target. Overall, the research seeks to uncover the molecular mechanisms behind the behavior of EGR1 and EGR2 in controlling inflammation-related genes and their significance in disease contexts.

Текст от CORDIS, на английски · Данни: CORDIS, © Европейски съюз

Цел на проекта

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.

Оригинален текст от CORDIS (на английски).

Участници

STICHTING AMSTERDAM UMC · AmsterdamКоординаторНидерландия