The Centre’s research is characterised by the continuum of basic through to clinical research with emphasis on the fields of reproductive neuroendocrinology and hormone-dependent cancer and in particular the physiological and pathophysiological role of hormones and their cognate G protein-coupled receptors (GPCRs). In these systems, the Centre’s research can be subdivided into three major themes. In all cases, there is a major emphasis on the development of new therapeutics or diagnostic tools:
- Theme 1: Interrogation of neuroendocrine axes:
Gonadotropin releasing hormone (GnRH) secreted from the hypothalamus is known as the master hormone regulator of the hypothalamic-pituitary-gonad (HPG) axis, which controls puberty, fertility and reproduction in humans. Several gene products have been shown to impact GnRH activity, with defects in these causing the reproductive dysfunction, hypogonadotropic hypogonadism (HH). GPCRs are an extremely important family of signalling molecules involved in the majority of endocrine hormone signalling. There are a vast number of GPCRs expressed in the hypothalamus which have the potential to be involved in, or impact, the secretion and function of GnRH. Through involvement in a large international consortia, we have access to a large cohort of patients suffering from HH of unknown etiology. Exome sequencing of these patients has revealed several novel mutations in GPCR genes not currently known to be involved in the control of reproduction/fertility and the Centre is responsible for examining the (non-)functionality of the mutant protein products of these genes in vitro and in vivo in order to determine whether the patient’s reproductive dysfunctions can be attributed to these mutations. Characterization of novel GPCR mutations implicated in HH will provide insight into the physiological and pathophysiological roles of the underlying systems involved in the neuroendocrine control of reproduction and may identify novel pathways or targets through which diagnostic tools or therapeutic agents for infertility and reproduction could be developed.
Prof Millar has also been working with Euroscreen, a biotech company in Belgium, in developing an antagonist of Neurokinin B, a hypothalamic hormone. Prof Millar hypothesised that a Neurokinin B antagonist would provide treatment for polycystic ovarian syndrome (which affects 30% of women) and hot flushes (affects 60-80% of post-menopausal women). This compound has now proven to be successful in reducing frequency and severity of menopausal hot flushes in a Phase II a clinical trial and a large-scale Phase II b trial is now being planned.
- Theme 2: Examination of genetic disruption of neuroendocrine receptors
A primary focus of the Centre’s research revolves around the breakthrough discovery that function can be restored to inactivating genetic mutations in human G-protein-coupled receptors (GPCRs), which are responsible for most cell communication. Dr Claire Newton and Dr Ross Anderson have fully characterised all human inactivating mutations in the luteinizing hormone receptor, the conduit for stimulation of the ovaries and testes, which have been identified in patients suffering from reproductive dysfunction. They found that most of the mutations result in a failure of the receptors to traffic to the cell surface, preventing interaction with their hormone signal and therefore rendering the receptors non-functional. They have also discovered a novel small-molecule compound (also called ‘pharmacological chaperone’) which is able to enter cells and stabilise such mutant receptors so that they express on the cell surface, therefore restoring their function. Clinical proof-of-concept studies are now being initiated with patients harbouring mutations which they have shown can be rescued in vitro.
- Theme 3: Investigation of the role of neuroendocrine hormones/receptors in hormone-dependent pathologies (e.g. cancer).
Cancer research investigates cancer progression and metastasis, especially within breast cancer. Previous work investigated the role of integrins in regulating gene expression as well as the role of phosphoinositides in cell adhesion and migration. Currently, we are interested in the role specific estrogen regulated G-coupled protein receptors play in the initiation of metastasis. The GPCRs GPER and KISS1R are both markers for poor prognosis in estrogen receptor positive breast cancers and may play direct roles in cell migration, invasion and metastasis. We are using biochemical and cell biological methods including fluorescence microscopy to determine the influence of these proteins on focal adhesion turnover, cytoskeleton organisation and migration. Another research highlight in the cancer field is the development of Gonadotropin-releasing hormone (GnRH) analogue-estrogen conjugates as novel drugs for prostate cancer which ameliorate side effects of hot flushes and loss of bone and libido, characteristic of current therapeutics. Preliminary in vitro analyses of these compounds have confirmed their activity and pre-clinical testing in rats is now being undertaken.