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Title: Studies on the role of formyl peptide receptors in pituitary and adrenal function
Author: Naughton, Vance
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2012
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The mechanism by which glucocorticoids (GCs) achieve negative feedback on the release of hypothalamo-pituitary-adrenal (HPA) axis hormones has long been under investigation. Annexin A1 (ANXA1) is a key mediator of the effects of GCs within the neuroendocrine and immune systems. Previous research suggested the negative feedback effect of the GC-ANXA1 system on the pituitary release of adrenocorticotrophic hormone (ACTH) was mediated via a member of the formyl peptide receptor (Fpr in rodents, FPR in humans) family. The present work tested the hypothesis that specific Fpr/FPR subtypes modulate both pituitary and adrenal function in terms of stress hormone (ACTH and corticosterone) secretion (following exposure to secretagogues CRH and ACTH or the inflammogen LPS in rats), and their tissue distribution (mice and rats) will itself be upregulated following inflammogenic stress (LPS in mice and rats, multiple sclerosis in human tissue). This was achieved through 1) immunohistochemical detection of FPR1, FPR2/ALX, and FPR3 in human anterior pituitary sections, and of green fluorescent protein (GFP) in HPA axis tissues from Fpr2/3-/-, GFP+/+ mice; 2) measurement of basal and stimulated ACTH and GC release from dispersed rat anterior pituitary and adrenal cells, incubated with agonists and antagonists for FPR1, FPR2/ALX and FPR3, namely, formyl-Met-Leu-Phe (fMLF), ANXA1 amino-acetylated peptide (ANXA1Ac2-26), Trp-Lys-Tyr-Met-Val-D-met (WKYMVm), haem-binding protein fragment (F2L), aspirin-triggered lipoxin A4 (15-epi-LXA4), and Trp-Arg-Trp-Trp-Trp-Trp (WRW4). These ligands were found to elicit a range of modulatory, concentration-dependent effects on pituitary ACTH and adrenal GC secretion. Evidence was found for the spatial distribution of: FPR3 and FPR2/ALX within the human anterior pituitary, and GFP (as a surrogate for Fpr2/3) colocalised with ACTH, growth hormone (GH), and prolactin (PRL) within the Fpr2/3-/-, GFP+/+ mouse pituitary. The findings contribute evidence in support of a role of Fpr/FPR subtypes and their ligands as modulators of pituitary and adrenal hormone release.
Supervisor: John, Christopher; Buckingham, Julia Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available