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Dimitris Grammatopoulos

Technical Summary

Stress hormones and homeostatic adaptive responses in feto-maternal pathophysiology

The overarching aim of our research programme is to elucidate how stress hormones of the Hypothalamo-Pituitary-Adrenal (HPA) endocrine system control feto-maternal symbiosis and how maternal disease can induce maladaptive responses that compromise health of mother and fetus development. In vertebrates the stress hormone system, which is conserved across evolution, is critical for organism survival by driving homeostatic adaptive mechanisms to environmental changes and regulating developmental plasticity. The main focus of our research is the corticotrophin releasing hormone (CRH), considered as the “first mediator” of the stress response. CRH is expressed in the placenta of higher primates only, and is thought to play important roles in normal pregnancy and labour, by regulating maternal and fetal adaptive responses. This system is also important in conditions associated with adverse pregnancy outcomes such as gestational diabetes, pre-eclampsia and intrauterine growth retardation (IUGR). We explore basic and clinical translational aspects of CRH actions in feto-maternal pathophysiology. Our fundamental studies aiming at dissecting molecular signaling mechanisms of the CRH receptors, especially mechanisms controlling a range of biological processes such as energy homeostasis, development of inflammatory responses and malignant transformation of cells leading to uncontrolled cell growth and cancer. We are particularly interested in pre- and post-transcriptional modifications such as mRNA splicing and protein phosphorylation and glycosylation that regulate cell responsiveness to CRH. We recently identified the presence of such a mechanism in breast cancer that allows cells to limit CRH actions by enhancing expression of aberrant CRH receptor variants.

In parallel translational studies, we investigate the molecular and biochemical signatures of HPA axis activity in order to understand the biological and genetic underpinnings of mood disorders such as depression developed during pregnancy and postpartum. We employ multidisciplinary approaches linking disease phenotype with hormonal and epigenetic biomarkers using advanced statistical methodologies and bioinformatics in order to develop algorithm-based multi-analyte clinical diagnostic tools.

Selected publications:

Lu B, et al. The corticotrophin-releasing factor/urocortin system regulates white fat browning in mice through paracrine mechanisms. Int J Obes (Lond). 2015 Mar;39(3):408-17.

Lal S, et al. Estrogen alters the splicing of type 1 corticotropin-releasing hormone receptor in breast cancer cells. Sci Signal. 2013 Jul 2;6(282):ra53.

Punn A, et al. Mapping structural determinants within third intracellular loop that direct signaling specificity of type 1 corticotropin-releasing hormone receptor. J Biol Chem. 2012 Mar 16;287(12):8974-85.

Markovic D, Grammatopoulos DK.Focus on the splicing of secretin GPCRs transmembrane-domain 7. Trends Biochem Sci. 2009 Sep;34(9):443-52.