Role of glucocorticoid signalling in stress adaptation

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The development of adaptive strategies to cope with a wide spectrum of stressors is fundamental to the overall fitness of an organism. Key players that orchestrate the stress response in vertebrates are corticosteroids, and their action can be mediated by two receptors, the glucocorticoid receptor (GR) and the mineralocorticoid receptor (MR). These corticosteroid receptors are evolutionarily conserved and are ubiquitously expressed in vertebrates. My research program aims to understand the mechanisms of glucocorticoid action, and the consequences of stress-related glucocorticoid signalling in adapting animals to stress. Despite the well characterized action of GR, almost nothing is known about the physiological role of MR in fish. Therefore, my overarching hypothesis is that MR signalling is essential for stress axis activation and can operate in a complementary fashion with GR in regulating the highly conserved glucocorticoid-mediated stress adaptation. In this 5-year proposal, my goal is to specifically explore the evolutionarily conserved role of MR in the perception and activation of the stress response, as well as the regulation of stress-related behaviour. My lab recently generated the GR and MR knockout mutants in zebrafish using CRISPR/Cas9 mutagenesis. Using these mutants, we will carry out loss of function studies to fully characterize the role of these receptors in modulating the stress coping mechanisms. We have also generated double GR,MR knockouts (MGR) in zebrafish, and these MGR mutants, in combination with my existing GR and MR mutants, will allow my lab to comprehensively determine the conserved action of corticosteroid receptors in mediating the glucocorticoid-related stress responses. The methodology will involve whole animal studies with zebrafish (wildtype and mutants) at various developmental stages, as well as tissue-specific studies, including liver, gill, heart, head kidney, skeletal muscle, and brain. The studies will determine the contribution of the corticosteroid receptor signalling in regulating the energy substrate re-partitioning associated with stress. The results from these studies will provide novel insights on stress coping mechanisms, and specifically the role of MR signalling in mediating the glucocorticoid effect in restoring homeostasis. Furthermore, the new tools, including receptor knockouts, we have generated will provide an ideal environment for training and collaboration, and will facilitate discoveries of novel pathways involved in stress adaptation. The results from this work will have an impact on all areas of fish stress research, including aquaculture and environmental effects monitoring. It will also have translational potential in the biomedical field, as knockout of either GR or MR in mammals is lethal. Finally, this proposal and the results generated will greatly impact our understanding of the evolutionary conserved role of glucocorticoids in mediating stress adaptation.