GPCR biology/pharmacological chaperone therapeutics (PIs: Dr R Anderson, Dr C Newton and Prof R Millar) Identification and analysis/characterisation of G protein coupled receptors (GPCR) mutated in patients who fail to progress through puberty.Investigation of the regulatory proteins involved in reproduction through the examination of genetic mutations linked to a failure to advance through puberty:.Development of an effective immuno-contraceptive vaccine for companion animals, livestock and wildlife.Characterisation and identification of novel non-peptide GHRHR agonists and antagonists for development as therapeutics for GH-related pathologies (e.g.Examining the integration and regulation of signal outputs from the hypothalamus and pituitary in physiological/pathophysiological conditions and identification of potential novel therapeutic targets (eg amenorrheic hyperprolactinemia with kisspeptin, polycystic ovarian syndrome and post-menopausal hot-flushes with Neurokinin B antagonists).Interrogation and therapeutic targeting of neuroendocrine axes:.This is a considerable advance, as rescuing function in mutant human GPCRs has only been achieved once and sets the scene for a new pharmacology in restoring function to a wide spectrum of disease arising from mutations in the large family of about 500 GPCRs in the human genome. A highlight is that they have now commenced studies in patients with inactivating mutations in the luteinizing hormone receptor. His group has demonstrated that they can restore function with cell- permeant small molecules for five mutant GPCRs. His group’s most recent focus is on rescuing function of inactivating mutations in human GPCRs which mediate 80% of all signalling in humans and animals. He developed kisspeptin antagonists as potential therapeutics in hormone-dependent diseases.
More recently he has focused on novel GPCRs regulating reproduction, appetite, inflammation, cell invasion and angiogenesis with a particular focus on the RFamides such as metastin/kisspeptin and gonadotropin-inhibitory-hormone, and NKB and prokineticins. His group's research on direct antiproliferative effects of selective GnRH analogues on tumour cells has revealed the novel concept of ligand-induced-selective-signalling by GnRH analogues (now called "biased signalling"), which has implications for improved selectivity in the development of new GnRH therapeutics and other GPCR targets. He has participated in, and led, a number of programmes developing GnRH analogues for use in a wide range of clinical pathologies. His laboratory delineated GnRH binding sites and the molecular mechanisms underlying receptor activation and coupling. He pioneered the discovery of the GnRH prohormone, novel GnRH structures, and the first cloning of the GnRH I and GnRH II receptors. Selected publications | Contact details | Group Membersįull Member, Institute of Infectious Disease and Molecular Medicine Department of Integrative Biomedical Sciences, Faculty of Health Sciences, UCT Professor and Director, Centre for Neuroendocrinology, University of Pretoria Research Fellow, Centre for Brain Discovery, University of Edinburgh, UK, Emeritus Professor, University of St Andrews.īob Millar's research focuses on peptide regulators of reproductive hormones.
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