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