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Is there a switch between prostamides and prostaglandins in women with dysmenorrhoea and heavy menstrual bleeding?


Project Description

Dysmenorrhoea, painful menstrual cramps, and heavy menstrual bleeding are common debilitating symptoms in women with or without an underlying pelvic pathology. Severity has been associated with high arachidonic acid metabolism and prostaglandin (PG) biosynthesis, which increase uterine tone, high amplitude contractions and ischaemia (Carrarelli et al., 2016). The endocannabinoid anandamide (AEA) is highly expressed in the uterus and is an indirect substrate for PG production. It is thought that shifting AEA hydrolysis in favour of prostamide formation is important for decidual remodelling, embryo implantation (Almada et al., 2016; Cui et al., 2017) and could offer pain relief (Sanchez et al., 2016). However, the complex interplay of AEA-related pathways during menstruation is poorly understood. The aim of this project is to characterise PGs, prostamides and their receptors according to menstrual phase in uterine health and disease.

Assays will be performed using human tissues from consenting women undergoing routine gynaecological surgery and from mouse models in line with Local Ethics and Home Office regulations. Lipidomics will be employed to profile PGs, endocannabinoids and other bioactive lipids, immersion will be performed for tissue contraction studies and histology, ICC and molecular techniques to assess receptor and protein expression. Findings will be correlated with clinical history and patient-reported symptoms. A cell-based modelling approach will also be used to identify the pharmacological effect of prostamides and PGs on cell metabolism and growth and to assess the value of potential therapeutic compounds. This preclinical approach should provide new insights into the paracrine pathways leading to dysmenorrhoea and heavy menstrual bleeding for potential future diagnostic and therapeutic developments.

For international students we also offer a unique 4 year PhD programme that gives you the opportunity to undertake an accredited Teaching Certificate whilst carrying out an independent research project across a range of biological, medical and health sciences. For more information please visit http://www.internationalphd.manchester.ac.uk.

Funding Notes

Candidates are expected to hold (or be about to obtain) a minimum upper second class honours degree (or equivalent) in pharmacology, biochemistry, biomedical sciences or relevant subject. A Master qualification in a similar area would be a significant advantage. Candidates with experience in bioanalysis, molecular biology or with an interest in in the physiology and pathophysiology of the female reproductive tract are encouraged to apply.

This project has a Band 2 fee. Details of our different fee bands can be found on our website (View Website). For information on how to apply please visit(View Website).

References

1. Almada, Cunha, Fonseca, Amaral, Piscitelli, Di Marzo, Correia-da-Silva, Teixeira (2016) Anandamide interferes with human endometrial stromal-derived cell differentiation: An effect dependent on inhibition of cyclooxygenase-2 expression and prostaglandin E2 release. Biofactors. 42(3): 277-86.
2. Carrarelli, Funghi, Bruni, Luisi, Arcuri, Petraglia (2016) Naproxen sodium decreases prostaglandins secretion from cultured human endometrial stromal cells modulating metabolizing enzymes mRNA expression. Gynecol Endocrinol. 32(4): 319-22.
3. Cui, Wang, Wang, Zhang, Xu, Jiang, Hao (2017) The correlation of anandamide with gonadotrophin and sex steroid hormones during the menstrual cycle. Iran HJ Basic Med Sci 20: 1268-74.
4. Glass, Hong, Sato, Mitchell (2005) Misidentification of prostamides as prostaglandins. J Lipid Res. 46(7): 1364-8.
5. Sanchez, Vigano, Mugione, Panina-Bordignon, Candiani (2012) The molecular connections between the cannabinoid system and endometriosis. Mol Human Reprod. 18(12): 563-71.

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