Research Focus:

1. The molecular pathways mediating the role of COX enzymes and prostaglandins in menstruation and epithelial cell function.


2. Prokineticin function in uterine physiology and associated pathologies .



1. The molecular pathways mediating the role of COX enzymes and prostaglandins in menstruation and epithelial cell function.

A pivotal role has been established for prostaglandins in mediating inflammatory and tissue-remodelling events in many diseases including chronic inflammatory diseases (such as those affecting the joints and bowel); allergy and asthma; atherosclerosis; and metabolic and degenerative diseases. These events involve modulation of the vascular and the immune systems. Non-steroidal anti-inflammatory drugs (NSAID) that inhibit the activity of COX enzymes (namely the COX-2 inducible form) showed promise in suppressing inflammation. However, these drugs are reported to increase risk of cardiovascular events, including thrombosis and stroke in some patients. Therefore, it has been suggested that alternative therapies which inhibit the synthesis of specific prostanoids (i.e drugs that target specific prostanoid synthase enzymes) or their signalling (i.e. drugs that target specific prostanoid receptors) may prove more useful therapeutically with few or no side effects.

Physiological processes such as menstruation display hallmark signs of inflammation. Exacerbated onset of inflammatory processes may contribute to the initiation and progression of non-malignant “benign” endometrial disorders/pathologies (such as menstrual disorders and endometriosis) and endometrial cancer. PGF2alpha and PGE2 are primary prostaglandins secreted by the endometrium and are recognised as important regulators of menstruation. Classically, the role of these prostaglandins in initiation of menses has been attributed to their potent effects on vascular tone and myometrial contractility. Our group and others have also shown that the synthesis and signalling of prostanoids is dysregulated in a number of endometrial disorders such as heavy menstrual bleeding (menorrhagia), dysmenorrhoea, endometriosis and cancer.

We and others have also shown elevated expression and signalling of EP receptors, such as EP2 and EP4, in endometrial pathologies. Our studies in endometrial cancers have revealed that in addition to up-regulation of EP receptors, there is significant and concomitant increase in the expression of other prostaglandin receptors such as the FP receptor. These receptors (EP and FP) are elevated and co-expressed in the same cell types in endometrial cancer including epithelial cells.

 Recent key scientific achievements of this programme of research

• Discovery that prostanoid receptor expression and signalling is dysregulated in endometrium of women with non-malignant (benign) endometrial pathologies and cancer.
  
  
• Established an important role for the EP and FP receptors in regulation of endothelial cell function, immune cell chemotaxis and tissue remodelling using in vitro and in vivo models

• Delineation of the diverse signalling pathways that are activated by the FP receptor to regulate expression of genes involved in vascular function, immune cell chemotaxis and tissue remodelling processes.
  
  
• Discovery that simultaneous activation of prostaglandin receptors (for example FP and EP receptors) initiates unique molecular pathways.
  
  
• Discovery that seminal plasma prostaglandins activate cervical and endometrial PGE2 receptors (EP2 and EP4) and drive the expression of inflammatory/angiogenic genes.
  
  Figure 1. (Click for full screen view and legend)

2. Prokineticin function in uterine physiology and associated pathologies

The prokineticins are two recently identified proteins with roles in physiological and pathological conditions. The names prokineticin 1 (PROK1) and prokineticin 2  (PROK2) were assigned to these proteins to reflect their actions in inducing specific and potent contractions of smooth muscles of the gastrointestinal tract.

Subsequently, a growth factor which induced a strong and reproducible mitogenic response in endocrine gland derived endothelial cells. The similar effects induced by this protein and VEGF led it to be named endocrine gland vascular endothelial growth factor (EG-VEGF). Although there are a number of similarities in the functions and control mechanisms of VEGF and EG-VEGF, the two factors are structurally unrelated. However, the amino acid sequences for PROK1 and EG-VEGF are identical and the nomenclature PROK1 has now been adopted officially for this protein. Prokineticins bind to two closely related G-protein coupled receptors (GPCR), known as prokineticin receptor 1 (PROKR1) and prokineticin receptor 2 (PROKR2). These receptors have a high degree of sequence identity (>85%). Although both receptors are able to bind PROK1 and PROK2, PROK2 shows a moderately higher affinity for both receptors than PROK1. This apparent non-selectivity of ligand receptor activation suggests that the expression profile and availability of the ligands and receptors in a particular organ/tissue determines which possible ligand-receptor pair is involved for a particular biological process. Several functions have been attributed to prokineticins that are of relevance to the reproductive system. These include regulation of angiogenesis, haematopoiesis and smooth muscle contractility. Several reports highlight a potential role for various ligand-receptor pairings of the prokineticin molecules in the regulation of these systems.

Prokineticins have been proposed to be important regulators of reproductive function. They are expressed in various human female reproductive organs including the ovary, uterus and in utero-placental tissues in pregnancy.

We were the first to describe prokineticin and prokineticin receptors in the endometrium and first trimester decidua. PROK1 is significantly elevated in the mid-secretory phase, while PROK2, PROKR1 and PROKR2 show no variation across the menstrual cycle. During pregnancy in first trimester decidua, PROK1 and PROKR1 expression are elevated further compared with non-pregnant endometrium. PROK1 and PROKR1 immunolocalize to stromal, endothelial and glandular epithelial cells of the endometrium. In the myometrium PROK1 and PROKR1 immunolocalize to smooth muscle and endothelial cells.
Our research has been focussed on investigating the roles of prokineticins in uterine function. Our data to-date strongly support a role for these novel molecules in key reproductive events.

Key Scientific Achievements

Figure 2. (Click for full screen view and legend)

Professor Jabbour’s group currently comprises two senior investigator scientists, Dr Roberto Catalano and Dr Kurt Sales, 2 career development fellows and four research support staff.

Member of the Editorial Board of Journal of Clinical Endocrinology and Metabolism, Reproduction, Journal of Endocrinology, Molecular and Cellular Endocrinology.

Long standing collaborations with numerous leading laboratories in the UK and overseas including South Africa , Europe and USA.

Member of numerous societies within the UK and USA.

Honorary Professor of The University of Edinburgh and honorary fellow of The University of Cape Town.

Member of the Scientific Advisory Board of the Jennifer Brown Research Fund and The Tommy’s Centre, The University of Edinburgh.

Member of the Executive Committee of the Centre for Reproductive Biology

Principal Collaborators

Professor Hilary OD Critchley, Professor Jane Norman, Professor Richard Anderson, Dr Fiona Denison, Dr Andrew Horne, Division of Reproductive and Developmental Sciences, University of Edinburgh

Dr Alistair Williams, Department of Pathology, University of Edinburgh

Dr Nik Hirani, Professor Adriano Rossi, Professor Jurgen Schwarze, Professor Christopher Gregory and Dr Kev Dhaliwal, Centre for Inflammation Research, Queen's Medical Research Institute, The University of Edinburgh

Dr Paddy Hadoke and Professor Brian Walker, Centre for Cardiovascular Science, Queen's Medical Research Institute, The University of Edinburgh

Professor Asgi Fazleabas, Michigan State University, USA
Dr Rob Sherwin, University of Cambridge, UK

Professor Aubrey Thompson, Mayo Clinic Comprehensive Cancer Centre, Florida, USA

Dr Leonid Nikitenko, University College London

Dr Arieh Katz, Department of Medical Biochemistry, University of Cape Town, South Africa

1. Evans J, Catalano RD, Brown P, Sherwin R, Critchley HOD, Fazleabas AR and Jabbour HN (2009).  Prokineticin 1 mediates fetal-maternal dialogue regulating endometrial leukaemia inhibitory factor. FASEB Journal 23: 2165-2175.
   
   
2. Sales, K.J., Grant, V., Cook, I.H., Maldonado-Perez, D., Anderson, R.A., Williams, A.R.W. and Jabbour, H.N. (2010). Interleukin-11 in endometrial adenocarcinoma is regulated by PGF2a-FP prostanoid receptor interaction via the calcium-calcineurin-Nuclear Factor of activated T cells pathway and negatively regulated by the regulator of calcineurin-1. American Journal of Pathology 176: 435-445.
   
   
3. Abera, A.B., Sales, K.J., Catalano, R.D., Katz, A.A. and Jabbour, H.N. (2010). EP2 receptor mediated cAMP release is augmented following activation of the calcium-calmodulin pathway by PGF-FP receptor interaction. Cellular Signalling 22: 71-79.
   
   
4. Wallace AE, Sales KJ, Catalano RD, Anderson RA, Williams ARW, Schwarze J, Wang H, Rossi AG and Jabbour HN (2009).  Prostaglandin F2a-F-Prostanoid receptor signalling promotes neutrophil chemotaxis via chemokine (C-X-C motif) ligand-1 in endometrial adenocarcinoma.  Cancer Research 69: 5726-5733.
   
   
5. Sales KJ, Boddy SC and Jabbour HN (2008).  F-prostanoid receptor alters adhesion, morphology and migration of endometrial adenocarcinoma cells. Oncogene 27: 2466-2477.
   
   
6. Smith OP, Jabbour HN and Critchley HOD (2007). Cyclooxygenase enzyme expression and E-series prostaglandin receptor signalling are enhanced in heavy menstruation.  Human Reproduction 22: 1450-1456.
   
   
7. Jabbour HN, Kelly RW, Fraser HM and Critchley HOD (2006).  Endocrine regulation of menstruation.  Endocrine Reviews 27: 17-46.
   
   
8. Jabbour HN, Sales KJ, Boddy SC, Anderson RA and Williams ARW (2005).  A positive feedback loop that regulates cyclooxygenase-2 expression and prostaglandin F2a synthesis via the F-series-prostanoid receptor and extracellular signal-regulated kinase 1/2 signalling pathway.  Endocrinology 146:4657-4664.
   
   
9. Sales KJ, List T, Boddy SC, Williams ARW, Anderson RA, Naor Z and Jabbour HN (2005).  A novel angiogenic role for prostaglandin F2a-FP receptor interaction in human endometrial adenocarcinoma. Cancer Research 65: 7707-7716.