- Prof Pierre Bouloux and Miss Helen Carr
- Dr Youli Hu
- Dr Bernard Khoo
- Dr Subathra Poopalasundaram
- Dr Aikaterini Theodoraki
- Dr Ploutarchos Tzoulis
Corifollitropin alfa trial in adult men in hypogonadotrophic hypogonadism (HH) (Prof. Pierre Bouloux and Miss Helen Carr)
The development of modified forms of FSH with prolonged biological half lives (Bouloux et al., 2001) has enabled this study to be undertaken, wherein patients with hypogonadotrophic hypogonadism (HH) wishing to have spermatogenesis induction will be treated with a novel recombinant FSH molecule endowed with a long duration of action and administered on a fortnightly basis, in combination with twice weekly Pregnyl. This offers the advantage of two FSH injections per month in contrast to the present requirement for twelve sc FSH administrations monthly. If we demonstrate successful spermatogenesis induction with this regimen, it will represent a significant advance in the treatment of male infertility caused by HH.
FGF signalling regulation by extracellular matrix protein, anosmin-1, in olfactory system development (Dr Youli Hu)
The olfactory system is unique within the CNS as olfactory sensory neurons are born outside of the brain and post-natally, continue to regenerate and project their axons towards the olfactory bulb (OB) where they form synapses with the dendrites of mitral/tufted cells throughout life. In humans, OB dysgenesis and disrupted GnRH neuron fate specification, migration, and axonal targeting lead to both anosmia and sexual immaturity, diagnostic hallmarks of the genetic developmental disorder Kallmann syndrome (KS). FGFR1 signalling and its functional regulator anosmin-1 mostly underlie the molecular basis for KS. We applied a wide range of molecular and cellular approaches and experimental models such as Surface Plasmon Resonance, in ovo electroporation in chick, OB explant and primary cell cultures, aiming to decipher the molecular mechanism as to how anosmin-1 modifies FGFR1 signalling complex formation and consequently how to direct activation of downstream signalling cascade via distinct pathways for the specific biological outcomes during OB and GnRH neuronal development. Our findings shed light on the mechanism of action of anosmin-1 on FGFR1 signalling, and have implications for possible molecular interventions for neuronal regeneration.
Splicing therapeutics for endocrine and metabolic diseases (Dr Bernard Khoo)
People with high levels of cholesterol are at higher risk of having heart attacks and strokes. Treatments that lower the levels of plasma cholesterol have been shown to protect against these diseases, thereby saving lives. Apolipoproprotein B, or ApoB, is a protein which carries cholesterol around in the bloodstream. I am investigating how we can use an antisense oligonucleotide to lower the level of blood cholesterol by modifying the way in which the body makes ApoB.
Specification and migration of gonadotrophin releasing hormone (GnRH) neurons (Dr Subathra Poopalasundaram)
The hypothalamic gonadotrophin releasing hormone (GnRH) neurons are a small group of neurons that regulate the reproductive axis. The release of GnRH from this population of neurons stimulates the release of lutenising hormone (LH) and follicle stimulating hormone (FSH) from the anterior pituitary and sets the scene for puberty. These neurons are specified within the olfactory placode, and then delaminate from this structure and migrate along the olfactory nerve, using it as a scaffold, to enter the telencephalon before populating the hypothalamus.
Hypogonadotropic hypogonadism (HH) results from a defect in specification/migration of GnRH neurons or secretion of GnRH and when this is coupled with anosmia (a lack of sense of smell), it is termed Kallmann syndrome (KS). More than 21 genes causing HH and KS have been identified accounting for about 60% of cases. Fibroblast growth factor (FGF) signalling relevant genes eg KAL-1 (anosmin), FGFR1, FGF8 and heparin sulphate 6-O-sulfotransferase play a key role in GnRH neuronal ontogeny. Other axon guidance molecules such as semaphorin-3A have also shown to be involved in the migrations of GnRH neurons.
However, these genes account for only a fraction of the KS patients seen. It should also be noted that such impaired migration could result from defects in the formation of the olfactory nerve, the scaffold upon which these neurons migrate, or from deficits within the GnRH neurons themselves. We aim to understand the molecules important for GnRH neuronal specification and how these cells exit the olfactory placode with a view to isolating new candidate molecules to screen in patients who do not show mutations in any of the thus far identified HH/KS genes.
Using the chick as a model organism we aim to study the specification and development of the GnRH neurons. The chick expresses all of the identified HH/KS genes and it is easily accessible to in ovo manipulations including genetic perturbations as well as ex vivo and in vitro analysis. Microarray technology has been used at various developmental time points which are important for GnRH ontogeny and a large number of genes have been identified. These are currently being characterised for their involvement in GnRH development.
Prof Anthony Graham
MRC Centre for Developmental Neurobiology, London
Heparan sulfate proteoglycans (HSPGs) and fibroblast growth factor (FGF) signaling in islet cells (Dr Aikaterini Theodoraki)
Heparan sulfate proteoglycans (HSPGs) exist in cell membranes and the extracellular matrix. HSPG has a core protein component, to which glycosaminoglycan side chains are attached. The glucosaminoglycan chains consist of disaccharides that can be sulfated in four different positions, creating a marked diversity in HS in different tissues. Specific motifs of HS modulate the binding of growth factors to their cognate receptors. HS co-localizes with extracellular amyloid deposits in humans with type 2 diabetes and evidence suggests a role for HS in insulin secretion. Although HS seems to modulate growth factor and their receptor interactions in the islet microenvironment, the intra-islet structures of HS in health or altered glucose homeostasis are currently unknown.
Using a variety of techniques we have shown distinct spacial distribution of HS motifs in islets in the adult, with mostly conserved motifs between rodents and humans. Our results suggest that beta cell HS is characterised by 2-O, 6-O and N-S sulfated moieties, whereas HS in alpha cells is low in 6-O groups. FGF1 and FGF2 are present in alpha cells, FGF1 is present in beta cells, whereas functional FGFRs are present in beta cells, but not in the alpha cell line aTC1-6. Our current data propose a novel role for alpha cells as a source of paracrine FGF ligands to neighbouring beta cells with specific cell-associated HS domains mediating the diffusion of paracrine ligands.
Hyponatraemia (Dr Ploutarchos Tzoulis)
Our clinical research is focused on various aspects of hyponatraemia. Hyponatraemia is the most common electrolyte disorder and is associated with significant morbidity and mortality. Our goal is to promote good clinical practice in the investigation and management of hyponatraemia with the aim of improving the outcomes of patients with hyponatraemia.
We have been conducting the 2 largest clinical studies in the field of hyponatraemia in the UK for the last 2 decades. Our clinical studies are focused on the management and outcomes of hyponatraemia in a 'real life setting'. We have undertaken a large case-control study of hyponatraemic patients' outcomes and we are conducting the first multi-centre study about the investigation and management of hyponatraemia in the UK. Ongoing studies are investigating novel ways of managing hyponatraemia with an aim to improve patients' outcomes.