Emeritus Professor Robert Millar

Receptor Biology Group

Emeritus Professor Robert (Bob) Millar PhD, MRC Path (Chem), FRCP Path (Chem)

Full 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. 

Bob Millar's research focuses on peptide regulators of reproductive hormones. He pioneered the discovery of the GnRH prohormone, novel GnRH structures, and the first cloning of the GnRH I and GnRH II receptors. His laboratory delineated GnRH binding sites and the molecular mechanisms underlying receptor activation and coupling. He has participated in, and led, a number of programmes developing GnRH analogues for use in a wide range of clinical pathologies. 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. 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. He developed kisspeptin antagonists as potential therapeutics in hormone-dependent diseases.

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. His group has demonstrated that they can restore function with cell- permeant small molecules for five mutant GPCRs. A highlight is that they have now commenced studies in patients with inactivating mutations in the luteinizing hormone receptor. 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.

Projects

  • Interrogation and therapeutic targeting of neuroendocrine axes:
    • 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). (PI: Prof R Millar)
    • Characterisation and identification of novel non-peptide GHRHR agonists and antagonists for development as therapeutics for GH-related pathologies (e.g. cancer, dwarfism and acromegaly). (PI: Dr C Newton) 
    • Development of an effective immuno-contraceptive vaccine for companion animals, livestock and wildlife. (PIs Prof R Millar and Prof Bertsinger) 
  • Investigation of the regulatory proteins involved in reproduction through the examination of genetic mutations linked to a failure to advance through puberty:
    • Identification and analysis/characterisation of G protein coupled receptors (GPCR) mutated in patients who fail to progress through puberty. (PIs: Dr R Anderson, Dr C Newton and Prof R Millar)

GPCR biology/pharmacological chaperone therapeutics

  • Identification of novel pharmacological chaperone therapeutics:
    • Identification, development and clinical study of novel pharmacological chaperones (PCs) able to rescue intracellularly retained disease-causing mutant GPCRs. (PI’s: Dr R Anderson, Dr C Newton and Prof R Millar)
    • Investigation into the mechanism of mutant GPCR intracellular retention and pharmacological chaperone rescue (PI: Dr C Newton) 

Cancer research

  • Investigation into the role of GPCR receptors and hormone ligands in the progression and behaviour of breast and prostate cancers
    • Investigation of the role of the alternative estrogen receptor GPER in the development of breast cancer and its regulation of metastatic processes. (PI: Dr I van den Bout) 
    • Investigation of the neuropeptide Kisspeptin and its cognate receptor KISS1R in breast cancer and prostate cancer. (PI: Dr I van den Bout) 
    • Development and evaluation of novel therapeutics for the treatment of prostate cancer treatment with reduced side effects. (PIs: Prof R Millar and Dr C Newton)

Bob has published over 450 articles in peer reviewed journals which have been cited over 23,000 times, generating an H-index of over 70. He has received many prestigious international and national awards. He is editor in chief of Neuroendocrinogy which has an impact factor of over 5.

Selected publications:

George JT, Hendrikse M, Veldhuis JD, Clarke IJ, Anderson RA, Millar RP. Effect of gonadotropin-inhibitory hormone on luteinizing hormone secretion in humans. (2017) Clinical Endocrinology 86(5):731-738

Skorupskaite K, George JT, Veldhuis JD, Millar RP, Anderson RA. Neurokinin 3 Receptor Antagonism Reveals Roles for Neurokinin B in the Regulation of Gonadotropin Secretion and Hot Flashes in Postmenopausal Women (2017) Neuroendocrinology

Pineda R, Plaisier F, Millar RP, Ludwig M. Amygdala Kisspeptin Neurons: Putative Mediators of Olfactory Control of the Gonadotropic Axis. (2017) Neuroendocrinology 104(3):223-238

Matjila M, Millar R, Van Der Spuy Z, Katz A. Elevated placental expression at the maternal-fetal interface but diminished maternal circulatory kisspeptin in preeclamptic pregnancies. Pregnancy Hypertension (2016) 6(1):79-87.

Newton CL, Anderson RC, Katz AA, Millar RP. Loss-of-function mutations in the human luteinizing hormone receptor predominantly cause intracellular retention. Endocrinology (2016) 157(11):4364-4377.

Raimondo JV, Tomes H, Irkle A, Kay L, Kellaway L, Markram H, Millar RP, Akerman CJ. Tight coupling of astrocyte pH dynamics to epileptiform activity revealed by genetically encoded pH sensors. Journal of Neuroscience (2016) 36(26): 7002-7013.

Maione L, Fèvre A, Nettore IC, Manilall A, Francou B, Trabado S, Bouligand J, Guiochon-Mantel A, Delemer B, Flanagan CA, Macchia PE, Millar RP, Young J. Similarities and differences in the reproductive phenotypes of women with congenital hypogonadotrophic hypogonadism caused by GNRHR mutations and women with polycystic ovary syndrome. Hum Reprod. doi: 10.1093/humrep/dey339. [Epub ahead of print]

RC Anderson, CL Newton, RP Millar. Small molecule follicle-stimulating hormone receptor agonists and antagonists (2018) Frontiers in Endocrinology 9, 757- 763.

Newton CL, Riekert C, Millar RP. Gonadotropin-releasing hormone analog therapeutics.(2018) Minerva Ginecol. 2018 Oct;70(5):497-515.

Anderson RC, Newton CL, Anderson RA, Millar RP. Gonadotropins and their analogues: current and potential clinical applications. (2018) Endocr. Rev. 39(6):911-937

Smith JT, Roseweir A, Millar M, Clarke IJ, Millar RP. Stimulation of Growth Hormone by Kisspeptin Antagonists in Ewes. (2018) J Endocrinol. 237(2):165-173. 

Clarke IJ, Li Q, Henry BA, Millar RP. Continuous Kisspeptin Restores Luteinizing Hormone Pulsatility Following Cessation by a Neurokinin B Antagonist in Female Sheep. (2018) Endocrinology. 159(2):639-646. 

Contact details:

Institute of Infectious Disease and Molecular Medicine
Division of Chemical & Systems Biology, UCT Faculty of Health Sciences
Observatory 7925
South Africa

Tel:  +27 21 406 6263 (Cape Town); +27 12 319 2501 (Pretoria)
Fax: +27 21 406 6061
Email: robertpetermillar@gmail.com

Alternate sites: www.up.ac.za/en/institute-for-cellular-and-molecular-medicine/article/2139137/centre-for-neuroendocrinology

www.medicalbiochemistry.uct.ac.za/

Group Members:

Dr Claire Newton
Dr Ross Anderson
Dr Iman van de Bout