A study of the impact of a natural gain-of-function substitution in the porcine glucocorticoid receptor on HPA axis regulation, glucocorticoid receptor signaling, and responsiveness to stress

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The hypothalamus-pituitary-adrenal (HPA) axis plays a pivotal role in the adaptation to stress, by coordinating the behavioral, endocrine, and immune responses. Efficient activation and timely termination of HPA axis response to stress, particularly release of the main effector hormones glucocorticoids (GC), promotes adaptive coping, and reduces the biological costs of stress which is beneficial for animal health and performance.Previously, we identified a unique, natural gain-of-function mutation Ala610Val in the porcine glucocorticoid receptor (GRAla61Val). Glucocorticoid receptor (GR), a ligand activated transcription factor, is the main transducer of physiological action of GC, and plays a central role in feedback regulation of the HPA axis. We discovered that the GRAla61Val substitution significantly downregulates activity of the entire HPA axis. It remains to be elucidated, how the neuroendocrine changes caused by the GRAla61Val substitution influence stress resilience and consequently production- and welfare-related traits under challenging conditions. In particular, in spite of the high relevance of GR signaling also in pathophysiological conditions, there is no information on the impact of GRAla610Val, and of GR hypersensitivity in general, on responses to immunological stressors, and on therapeutic efficacy of GC-based drugs in this context. Therefore, in the proposed project we aim to explore the impact of GRAla610Val on the temporal dynamics of the immune, neuroendocrine, behavioral and metabolic responses to endotoxin (LPS) challenge serving as a model of acute bacterial infection and inflammation. Furthermore, we aim to exploit this immune challenge to examine, whether GR hypersensitivity induced by GRAla610Val leads to higher sensitivity of the carriers to exogenous glucocorticoids in vivo. Finally, to better understand the observed phenotypic consequences of GRAla610Val and to gain novel insights into HPA axis regulation and GR signaling pathway, gene expression changes caused by GRAla610Val in the central branch of the HPA axis and in relevant glucocorticoid-target tissues (peripheral blood mononuclear cells, liver) will be explored by holistic transcriptome analyses.Besides expanding the current knowledge on HPA axis biology in pigs and on GR hypersensitivity in general, the project results will have direct implications for pig breeding towards higher resilience and also for the improvement of GC-based therapy of inflammatory diseases.