Glucocorticoids, the brain-endocrine-host defence interface
Professor Julia C Buckingham
Research interests:
The hypothalamo-pituitary-adrenocortical (HPA) axis plays an essential role in the maintenance of homeostasis. In normal circumstances its activity is tightly regulated and, hence, the circulating levels of glucocorticoids (GCs) are maintained within narrow limits. Modest disturbances in GC secretion/activity are however not uncommon and are increasingly implicated in the pathogenesis of a variety of diseases including depression, neurodegenerative disease, autoimmune / inflammatory disorders, hypertension, type 2 diabetes mellitus and obesity. Understanding the mechanisms that regulate the secretion and activity of glucocorticoids is therefore of fundamental importance.
Increasing evidence suggests that abnormalities in the GC negative feedback mechanisms are an important cause of disturbances in HPA activity. However, the molecular bases of these feedback mechanisms are far from fully understood and, hence, so too is the aetiology of disrupted feedback control. Our key goals are
• To understand the molecular mechanisms by which the steroids suppress the HPA axis in adulthood. In particular we aim to characterise the prompt effects of the steroids on peptide release which determine the magnitude and duration of the stress response. These actions are critical to the control of homeostasis in stress and are quite distinct from well characterised long-term effects of steroids on the expression of the genes encoding ACTH and its hypothalamic releasing factors.
• To determine the extent to which the molecular mechanisms effecting the prompt actions of GCs in the neuroendocrine system are used by GCs in other target tissues (e.g. the host defence system, neurones, microglia and astrocytes, the reproductive system, liver and adipose tissue).
• To understand the roles of GCs in the development of the brain-neuroendocrine system and to explain the mechanisms by which inappropriate exposure to GCs or stress during critical stages of development cause long-term functional and morphological changes which predispose the individual to disease.
Together, the data from these studies will enhance our understanding of the mechanisms by which GCs regulate healthy tissues and contribute to disease processes. They will thus provide important leads for the development of clinically effective drugs devoid of the harmful effects associated with GCs.
Key achievements in the last decade
Group Members:
Dr Egle Solito
Dr Christopher John
Mr Nicholas Buss
External links:
William Harvey Research Institute
Professor Roderick J. Flower, FRS
Professor Mauro Perretti
Department of Human Anatomy and Genetics, University of Oxford
Professor John Morris
Dr Helen Christian
Department of Veterinary Medicine, University of Cambridge
Dr Clare Bryant
Examples of recent publications:
Warne JP; John CD; Christian HC; Morris JF; Flower RJ; Sugden D; Solito E; Gillies GE; Buckingham JC. (2006)
Gene deletion reveals roles for annexin A1 in the regulation of lipolysis and IL-6 release in epididymal adipose tissue.
Am J Physiol Endocrinol Metab. 291: E1264-E1273
Post-translational modification plays an essential role in the translocation of annexin A1 from the cytoplasm to the cell surface.
Solito E, Christian HC, Festa M, Mulla A, Tierney T, Flower RJ, Buckingham JC
FASEB J 20(9):1498-1500 Jul 2006
Correlation between the antiinflammatory protein annexin 1 (lipocortin 1) and serum cortisol in subjects with normal and dysregulated adrenal function.
Mulla A, Leroux C, Solito E, Buckingham JC
J Clin Endocrinol Metab 90(1):557-562 Jan 2005
Aberrant inflammation and resistance to glucocorticoids in annexin 1-/- mouse.
Hannon R, Croxtall JD, Getting SJ, Roviezzo F, Yona S, Paul-Clark MJ, Gavins FN, Perretti M, Morris JF, Buckingham JC, et al.
FASEB J 17(2):253-255 Feb 2003
Dexamethasone induces rapid serine-phosphorylation and membrane translocation of annexin 1 in a human folliculostellate cell line via a novel nongenomic mechanism involving the glucocorticoid receptor, protein kinase C, phosphatidylinositol 3-kinase, and mitogen-activated protein kinase.
Solito E, Mulla A, Morris JF, Christian HC, Flower RJ, Buckingham JC
Endocrinology 144(4):1164-1174 Apr 2003
http://www.sciencedirect.com/science/journal/10432760
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