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(EPSRC DTP) Modelling the network of bioactive lipids involved in inflammatory reactions

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  • Full or part time
    Prof A Nicolaou
    Prof R Breitling
  • Application Deadline
    No more applications being accepted
  • Competition Funded PhD Project (European/UK Students Only)
    Competition Funded PhD Project (European/UK Students Only)

Project Description

Bioactive lipids are key players in the inflammatory and immune reactions that modulate the function of various cell types and organs. The network of bioactive lipid is complex, with many enzymes and metabolites involved [1]. Many of the metabolic pathways that regulate the formation of bioactive lipids have been targeted for the development of anti-inflammatories, whilst others are explored for their role in unwanted adverse reactions and toxicity [2].
In this project, we will create a quantitative computational model of some key metabolic pathways underpinning the role of bioactive lipids in skin inflammation. This in silico model will allow us to explore the interaction of different lipid cascades in response to stimuli selected to represent physiological, pathophysiological and environmental conditions. The model will also allow us to explore the impact of systemic interventions such as nutritional supplementations that have the ability to alter the prevalence and balance of cellular lipids, reduce inflammation and create a protective environment.
We will use an existing unpublished generic model of the target metabolic pathways as our starting point, and expand its predictive power by incorporating cell type-specific experimental data and information on transcriptional and translational dynamics of the system. We will also gather experimental data from human skin cells grown in culture and use mass spectrometry-based lipidomics to measure an array of lipid metabolites, estimate reaction rates and enzyme kinetics. We will further refine the model, especially to increase its ability to predict long-term effects of adverse stimuli, by integrating proteomics and/or transcriptome dynamic data. This information on lipid networks will then be processed using a new modelling strategy that is based on explicit consideration of parameter uncertainty and permits robust assessment of the confidence interval for all aspects of the predicted system behaviour [3].
The student will join a multidisciplinary team of researchers at the University of Manchester, with expertise in lipid and skin biology, systems biology, mass spectrometry and bioanalysis. The project provides a unique opportunity to work at the interface of chemistry and biology, on a project that has great potential to generate novel information applicable to biomedical research with focus on inflammatory skin diseases, and can support the development of novel treatments and therapeutics. Through the supervisors’ internal and external collaborations and research activities, the student will be exposed to academic and industrial research, and will have the opportunity to develop skills valued in a number of potential career paths.

References
1. G Astarita, AC Kendal, EA Dennis, A Nicolaou. Targeted lipidomic strategies for oxygenated metabolites of polyunsaturated fatty acids (2015) Biochim Biophys Acta 1851:456-468.
2. SA Murphy, A Nicolaou. Lipidomics applications in health, disease and nutrition research (2013) Mol Nutr Food Res 57:1336-46.
3. A Tsigkinopoulou, A Hawari, M Uttley, R Breitling R. Defining informative priors for ensemble modeling in systems biology (2018) Nature Protoc 13:2643-2663.

Entry Requirements
Applications are invited from UK/EU nationals only. Applicants must have obtained, or be about to obtain, at least an upper second class honours degree (or equivalent) in a relevant subject.

On the online application form select PhD Cell Biology. For information on how to apply for this project, please visit the Faculty of Biology, Medicine and Health Doctoral Academy website (https://www.bmh.manchester.ac.uk/study/research/apply/)

Funding Notes

EPSRC DTP studentship with funding for a duration of 3.5 years to commence in September 2019. The studentship covers UK/EU tuition fees and an annual minimum stipend (£15,009 per annum 2019/20). Due to funding restrictions the studentship is open to UK and EU nationals with 3 years residency in the UK.

As an equal opportunities institution we welcome applicants from all sections of the community regardless of gender, ethnicity, disability, sexual orientation and transgender status. All appointments are made on merit.

References

[1] M Cummings, KA Massey, G Mappa, N Wilkinson, R Hutson, S Munot, S Saidi, D Nugent, T Broadhead, AI Wright, S Barber, A Nicolaou, NM. Orsi. Integrated eicosanoid lipidomics and gene expression reveal decreased prostaglandin catabolism and increased 5-lipoxygenase expression in aggressive subtypes of endometrial cancer (2019) The Journal of Pathology 247:21-34

[2] J Newson, MP Motwani, AC Kendall, A Nicolaou, GG Muccioli, M Alhouayek, M Bennett, R Van De Merwe, S James, R PH De Maeyer, DW Gilroy. Inflammatory resolution triggers a prolonged phase immune suppression through COX-1/mPGES-1-derived prostaglandin E2 (2017) Cell Rep. 20:3162-3175

[3] AC Kendall, SM Pilkington, G Sassano, LE Rhodes, A Nicolaou. N-acyl ethanolamide and eicosanoid involvement in irritant dermatitis (2016) Br J Dermatol 175:163-71.

[4] A Tsigkinopoulou, SM Baker, R Breitling. Respectful modelling: Addressing uncertainty in dynamic system models for molecular biology (2017) Trends Biotechnol. 35:e0171324

[5] A Tsigkinopoulou, A Hawari, M Uttley, R Breitling. Defining informative priors for ensemble modeling in systems biology (2018) Nature Protoc. 13(11):2643-2663.



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