Research objectives and content
The purpose of the study is to investigate the significance of adenylyl cyclase and phosphodiesterase isotypes expressions in the secretory activity of anterior pituitary corticotrophs. Under stress, mammals secrete corticotropin releasing factor (CRF) which stimulates corticotrophs secretion via adenylyl cyclase activation and cAMP accumulation. Coupling CRF with its receptor may activate one or more cyclase isotypes. The latter are differentially regulated with regard to corticotroph stress-related second messengers (G protein, intracellular calcium ions, protein kinase C). One recently cloned adenylyl cyclase appears to be fundamental with respect to the efficiency of corticosteroid negative feedback. This isotype profile seems altered in the brain and the pituitary by stressors. Similar considerations apply for phosphodiesterases degrading cAMP. The host laboratory has shown the presence of calcium/calmodulin-regulated and rolipram-sensitive phosphodiesterase activity in tumoral corticotrophs, but nothing is known about normal cells.
In principle, the shunting of cAMP metabolism onto pathways independent of calcium ions should render the ACTH response resistant to glucocorticoid inhibition. Preliminary works support this hypothesis. In view of the well known pathological changes of glucocorticoid feedback in variety of psychiatric and endocrine disorders, it is of considerable importance to identify and characterise the elements of cAMP metabolism in adenohypophysial corticotroph cells.
Training content (objective, benefit and expected impact)
The proposed work should shed light on the molecular mechanism(s) of escape from corticosteroid feedback at the pituitary level, which may also prove to be relevant for nerve cells. The applicant will be provided an opportunity to train in molecular biological techniques and biochemical chauactelisation of signal transduction pathways that will complete his knowledge in human cell culture and single cell imaging.
Links with industry / industrial relevance (22)
No link with industry