H2020Индивидуална стипендия2021–2022

MeRGeR · Physiological significance of the glucocorticoid and mineralocorticoid receptor signalling in the innate immune system

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

Период: 2021-01-01 → 2022-12-31
Финансиране от ЕС: 175 572 €
Участници: 1
Схема: MSCA-IF

Линиите свързват координатора с партньорите.

Накратко на български

Минералокортикоидните рецептори и тяхното влияние върху имунния отговор се анализират чрез модели с рибки зебра. Разбирането на взаимодействието между тези рецептори помага да се разбере как стресът влияе върху имунитета на човека.

Този кратък обзор е генериран от изкуствен интелект

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

Резултати накратко

Physiological significance of the glucocorticoid and mineralocorticoid receptor signalling in the innate immune system

The purpose of the MeRGeR project was to unravel the role of the mineralocorticoid receptor (MR) in the immune response. This receptor is important in mediating the effects of cortisol, a key stress hormone in humans. However, prior to this project, the effects of cortisol on the immune system were primarily attributed to the other receptor of cortisol, the glucocorticoid receptor (GR) and very little was known about the immunomodulatory effects of MR. Determining how these receptors modulate the immune system, both independently and together is essential to our understanding of how stress impacts our immunity. Given the ubiquitous nature of stress, and the impact that it has on our society at both an individual and population level understanding the interaction between stress and the immune system is of strategic importance. To determine the role of MR in the immune system, we designed an interdisciplinary approach that combined advanced microscopy with novel in vivo models. The first objective was to determine the role of MR in modulating the inflammatory response. This objective was completed using the zebrafish animal model were I characterized the role of MR both during immune system development and in response to an inflammatory stimulus. The overall conclusion of this objective was that MR promotes the immune response, which was in contrast to the activation of GR, which was primarily anti-inflammatory. The aim of the second objective was to determine how MR and GR functionally interact to alter gene expression. Here we also used zebrafish as a model, as they are the only major model organism that can harbour a complete loss of GR and MR. Therefore, we were provided with a unique opportunity to assess the interaction of GR and MR in the whole animal. To do this we introduced mutated forms of GR and MR that could either only interact with themselves (homodimer) or each other (heterodimer). The conclusions of this objective were that GR and MR can indeed interact, and that this interaction has physiological and immunological significance. Overall, the publications that will be generated from this project will have considerable impact on the current paradigm of cortisol action in the immune system, how we understand stress, and in extending our understanding of the molecular actions of immunomodulating glucocorticoid drugs.

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

Цел на проекта

Glucocorticoids, such as cortisol, play an essential role in our stress response. Cortisol signals through two receptors, the glucocorticoid receptor (GR) and the mineralocorticoid receptor (MR), and it has profound effects on the immune system. To date, much of the research on cortisol action has focused on the function of GR, but almost no work has been done on the function of MR. My main aim is to unravel the role of MR in mediating the effects of cortisol on the immune response, and I would like to answer two questions: 1) How does MR activation modulate the inflammatory response? 2) How do MR and GR functionally interact to alter gene transcription? I will use an interdisciplinary approach. The first question will be answered using the zebrafish animal model, and I will determine the role of MR in wounding-induced leukocyte migration in zebrafish larvae and study the mechanism of action of MR in activated macrophages. The second question will be answered using cultured macrophages, and I will determine the occurrence of MR/GR heterodimers using biophysical approaches, and establish a functional role of the heterodimers. The outcome of this project will have a considerable impact on the current paradigm of glucocorticoid action in the immune system, and extend our understanding of the molecular actions of immune-modulating glucocorticoid drugs. My training objectives are: 1) Broadening my expertise in endocrine research using the zebrafish model system. 2) Expanding my toolbox using cell culture-based approaches and biophysics. 3) Developing complementary skills required for the management and organization of an academic research group. Furthermore, I will strengthen my scientific track record and network. The project will be performed at the Institute of Biology of Leiden University, and implementation of the project in that environment will ensure a unique position for me to run this project successfully, receive appropriate training and advance my career.

Оригинален текст от CORDIS (на английски).

Участници

UNIVERSITEIT LEIDEN · LeidenКоординаторНидерландия