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Title: RF-Amide Neuropeptides in the Control of the Hypothalamo-Pituitary-Gonadal Axis.
Author: Curtis, Annette Elizabeth
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2008
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Abstract:
Kisspeptin and RFRP-3 are members of the RF-amide family, neuropeptides characterised by an Arg-Phe-NH2 motif at their C-terminus. This thesis investigates the role of kisspeptin and RFRP-3 in HPG axis regulation and the role of kisspeptin in prostate cancer. First described as anti-metastatic factors, the kisspeptins have been more recently shown to stimulate the hypothalamic-pituitary-gonadal (HPG) axis via interaction with the GPR54 receptor. I have designed 21 analogues of kisspeptin-10, and investigated their bioactivity in vitro and in vivo. I have determined the amino acids critical to the binding of kisspeptin-10 to GPR54 using receptor binding assays. In vitro and in vivo studies identified one analogue, ANA19, with a longer acting stimulatory effect on the HPG axis than kisspeptin-10. As a GPR54 superagonist, ANA19 presents an opportunity to exploit the HPG-stimulating and anti-metastatic properties of kisspeptin as a potential therapy for reproductive dysfunction and endocrine cancers such as prostate cancer. The role of kisspeptin in prostate cancer was investigated using three human prostate cancer cell lines, all of which were found to release kisspeptin. However, circulating levels of kisspeptin men with prostate cancer were within normal ranges. Further research will help determine whether kisspeptin may playa role in the regulation of prostate cancer. I have investigated the effect of peripheral and central administration of RFRP-3, the rodent homologue of avian gonadotrophin inhibitory hormone (GnIH), on the HPG axis in normal and orchidectomised male rats. I found no effect of RfRP-3 on HPG axis parameters or food intake at any dose or time point investigated. Further study is required to elucidate the role of RFRP-3 in neuroendocrine regulation in rodents. These studies have studied the biological actions of kisspeptin and RFRP-3, two key members of the RF amide family on the HPG axis, and have identified a GPR54 superagonist which may have therapeutic potential.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.490266  DOI: Not available
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