Fully funded Exeter/Swansea (BBSRC SWBio DTP) PhD Studentship: Spatial and temporal resolution of the cellular (oxy)lipidome and its relation to inflammatory cell function

This studentship is funded by the Biotechnology and Biological Sciences Research Council (BBSRC) as part of the South West Biosciences Doctoral Training Partnership (SWBio DTP).

Start date: October 2021

Subject areas: Genetics, biochemistry, lipid metabolism, mitochondria, immunology

Supervisors:

- Professor Helen Griffiths (lead supervisor, Swansea University)
- Dr Nick Jones (Swansea University)
- Professor Andrew Crosby (lead supervisor, Exeter University)
- Dr Emma Baple (Exeter University)

Inflammation is essential; it provides the body’s first defence against infectious agents and promotes tissue repair after injury. To generate the energy necessary to kill pathogens and enable healing, immune cells normally switch their metabolic substrate requirements and mitochondrial activity. However, with age, inflammation becomes less well-controlled and infections tend to be prolonged, with scarring and increased morbidity. Associated with this, mitochondria are less efficient in immune cells from older adults. To make matters worse, inflammation may also accelerate the ageing process itself.

Increasing evidence indicates that older adults and people with metabolic disease have been most at risk from uncontrolled inflammation e.g. cytokine storms, following covid-19 infection linking ageing metabolism and inflammation. It is timely to understand more about metabolic substrate use by immune cells from older people and whether this impacts on inflammatory cell activity. Recent studies from the Griffiths’ group showed that older adults have a specific elevated pattern of fatty acids in the blood that correlate with inflammation. We have also observed that specific oxysterols are highly positively correlated with biological age in the plasma healthy people. Others have shown that oxysterols and phospholipids can have both pro- and anti-inflammatory effects but whether this is affected by age is unknown.

In parallel, the Crosby/Baple group have identified mutations in specific genes that regulate oxysterol and phospholipid levels. They have generated stable knockdowns in neuronal cells that exhibit altered mitochondrial metabolism. The two groups have worked together to develop new methods that enable measurement of oxysterols in different subcellular compartments in immune cells.

The aim of this project is to bring together the expertise of both groups in Exeter and Swansea Universities in an interdisciplinary investigation of (oxy)lipid metabolism in immune cells to explore their relationship with inflammation and ageing.

The first objective of the studentship will be stably knockdown and overexpress genes involved in (oxy)lipid metabolism in macrophage cell lines. Macrophage function in response to challenge, will be explored in each of the mutant models to understand the importance of these pathways.

The second objective of the project will be to establish a metabolic model in activated macrophages that uses stable isotopically-labelled tracer macronutrients. This will identify regulatory metabolic nodes during inflammatory cell activation and resolution.

The final objective of the project will be to study oxysterol metabolism in healthy older and younger adults. Together this new knowledge may help to prevent inflammageing and prolong health-span.

Eligibility
Academic criteria
- Applicants for a studentship must have obtained, or be about to obtain, a First or Upper Second Class UK Honours degree, or the equivalent qualifications gained outside the UK, in an appropriate area of science or technology. Applicants with a Lower Second Class degree will be considered if they also have a Master’s degree or have significant relevant non-academic experience.

- In addition, due to the strong mathematical component of the taught course in the first year and the quantitative emphasis in our projects, a minimum of a grade B in A-level Maths or an equivalent qualification or experience is required.

- We would normally expect the academic and English Language requirements (IELTS 6.5 overall with 5.5 in each component) to be met by point of application. For details on the University’s English Language entry requirements, please visit – http://www.swansea.ac.uk/admissions/english-language-requirements/

Equivalent qualifications/experience
- Physics A-level (grade B and above). Undertaking units as part of your degree that have a significant mathematical component (significant mathematical component examples include; maths, statistics, bioinformatics).

- Applicants must ensure they highlight their Maths background within their application and to upload any supporting evidence.

Residence criteria
-Fully funded studentships are available for Home students.

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