My research focuses on the action of the glucocorticoid receptor, which is an intracellular receptor that belongs to the family of steroid receptors. These receptors act like transcription factors upon activation by a ligand, by activating or repressing the transcription of target genes. The glucocorticoid receptor mediates the effects of glucocorticoid hormones like cortisol, which are secreted by the adrenal gland after stress and in a diurnal rhythm, and affect a wide range of systems like our metabolism, immune system, growth, and behavior. The glucocorticoid receptor is also activated by synthetic glucocorticoids like dexamethasone and prednisolone, which are widely used to treat immune-related disorders like asthma and rheumatoid arthritis. We study the molecular mechanisms of glucocorticoid receptor action in cell lines, but also in vivo, using the zebrafish as a model system. I have two main research themes:
1. Advanced imaging of glucocorticoid receptor activity
Although it is known that GR (like all steroid receptors) acts as a transcription factor by binding to specific sequences in our genome, it is largely unknown how GR finds these sequences and what happens to the receptor after DNA binding. In order to gain more insight into the intranuclear behavior of GR, we study the GR in the nucleus of a living cell using single-molecule microscopy techniques. This is done in collaboration with Prof. Dr. Thomas Schmidt and Dr. John van Noort of the Leiden Institute of Physiscs. Using our detailed analysis we are able to distinguish specific subpopulations of GR molecules and investigate the role of these populations in the process of transcription initiation.
2. Mechanisms of glucocorticoid receptor action in zebrafish
Like all vertebrate animals, zebrafish express a GR that mediates the effects of glucocorticoid hormones. The zebrafish GR is highly similar to its ortholog in humans and therefore we use the zebrafish as a model organism to unravel the molecular mechanisms of GR action in vivo. We study the immune-suppressive effects of GR in collaboration with Prof. Dr. Annemarie Meijer, using zebrafish inflammation and infection models. Furthermore, we are studying individual variation in the regulation of cortisol secretion. We have found several genes to be involved in the negative feedback of cortisol on its own production and we are investigating the cortisol secretion of zebrafish with different ‘personalities’.
Teaching
Following my expertise in advanced imaging technology and my role as coordinator of the Microscopy Unit of the Institute of Biology, I am responsible for the coordination of the 2nd year BSc course Microscopy and Imaging. In addition, I am coordinator of the course Medical Biotechnology, which is part of the minor Biotechology, and I give guest lectures on steroid signaling in other courses, also outside the Biology curriculum of Leiden University. Furthermore, numerous undergraduate students have found their way to my group for BSc and MSc thesis projects.
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