Postgraduate research opportunities

Control of Human Inflammatory Responses and Cell Pathology mechanisms by Prostanoid and endocannabinoid receptors

Immunology, immunopharmacology inflammatory/ metabolic cell pathology

Number of places

1

Opens

14 February 2020

Deadline

31 March 2021

Duration

36 Months

Eligibility

Honours degree or masters in either Immunology, Biochemistry or Pharmacology

Project Details

Prostaglandins are mediators of inflammation (derived from arachidonic acid) that can control inflammatory/ cytokine responses, via negative-feedback regulation. PGE2 is one of the most potent so far studied [1, 2], and can completely abolish many immune cell activities. They are also a primary cellular defence mechanism to allows cells to survive pathogenic stimuli [3]. TNF-a can induce cell-death directly in a wide variety of cells. This can be prevented by PGE2 but related metabolites have not been characterised. There are many other prostaglandins such as PGD2, PGE2-ethanolamide (thought to be derived from arachidonyl-ethanolamide) [4] and the more recently discovered 15-deoxy-PGJ2. This raises the questions, do these other PGs, that are present during immune responses, also regulate responses ? This project will study the effects of the new PGs and their precursor fatty acids on cytokine release (including TNF-a) from human monocytic cells (and other immune cells). Recently we showed that the EP4 receptor can control other PG receptors in a cyclic AMP-dependent/ gene expression manner [5, 6]. Their effects on TNF-induced cell death will also be studied along with their actions on the expression of key receptors and enzymes. The spectrum of fatty acid metabolites produced following immune activation in response to different pathogen pathways will be investigated. The signalling/ receptor systems by which these lipids induce their effects will be evaluated using drugs which interfere with the signalling systems, and also by directly measuring the levels of intracellular mediators. It will be attempted to localise the sequence of interactions of intracellular processes (expression of enzymes) during the development of inflammatory activation (using imaging systems to track fluorescent dyes) in response to diverse stimulatory pathways using different toll-like receptor ligands.

 

Techniques used:

Immunoassay, imaging technologies/ fluorescence microscopy, flow cytometry, cell isolation/ cell sorting, quantitative PCR to track expression of various key enzymes. Lipidomics evaluation of the spectrum of mediators produced.

Funding Details

Applicant will need to self-fund, find sponsorship for tuition and bench fees of £9000 per annum for duration of studies

Supervisor

Primary Supervisor:  Dr D. Rotondo

Email:   d.rotondo@strath.ac.uk

Further information

 

1. Davidson J. Higgs W. Rotondo D. (2013). Eicosapentaenoic acid suppression of systemic inflammatory responses and inverse up-regulation of 15-deoxyDelta(12,14) prostaglandin J2 production. Br J Pharmacol 169, 1130-1139.

 

 2. Brown, K. L. Davidson J. and Rotondo D. (2013) Characterisation of the prostaglandin E2-ethanolamide suppression of tumour necrosis factor-alpha production in human monocytic cells. Biochim Biophys Acta 1831, 1098-1107

3. Brown I. Cascio M.G. Rotondo D. Pertwee R.G. Heys S.D. Wahle K.W. (2013). Cannabinoids and omega-3/6 endocannabinoids as cell death and anticancer modulators. Prog Lipid Res 52, 80-109.

 

4  Davidson, J. Rotondo, D. Rizzo M. and Leaver H.A. (2012) Therapeutic implications of disorders of cell death signalling: membranes, micro-environment, and eicosanoid and docosanoid metabolism. Br. J. Pharmacol . 166, 1193-1210.

 

 5. Kashmiry, A. Tate R. Rotondo G. Davidson J. and Rotondo D. (2018) The prostaglandin EP4 receptor is a master regulator of the expression of PGE2 receptors following inflammatory activation in human monocytic cells. Biochim Biophys Acta (Mol & Cell Biol of Lipids) 1863, 1297-1304.

6. Brown I, Lee J, Sneddon AA, Cascio MG, Pertwee RG, Wahle KWJ, Rotondo D, Heys SD. (2019) Anticancer effects of n-3 EPA and DHA and their endocannabinoid derivatives on breast cancer cell growth and invasion. Prostaglandins Leukot Essent Fatty Acids. In press https://doi.org/10.1016/j.plefa.2019.102024

 

Contact us

Primary Supervisor:  Dr D. Rotondo

Email:   d.rotondo@strath.ac.uk