Supervisors

Lead Supervisor:  Dr Khushboo Borah Slater University of Exeter, Department of Biosciences

Co-Supervisors:  

Professor Valerie O'Donnell Cardiff University, Department of of Infection and Immunity

Professor Jean Van Den Elsen University of Bath, Department of Life Sciences

The GW4 BioMed2 MRC DTP is offering up to 21 funded studentships across a range of biomedical disciplines, with a start date of October 2025.

These four-year studentships provide funding for fees and stipend at the rate set by the UK Research Councils, as well as other research training and support costs, and are available to UK and International students.

About the GW4 BioMed2 Doctoral Training Partnership

The partnership brings together the Universities of Bath, Bristol, Cardiff (lead) and Exeter to develop the next generation of biomedical researchers. Students will have access to the combined research strengths, training expertise and resources of the four research-intensive universities, with opportunities to participate in interdisciplinary and 'team science'. The DTP already has over 90 studentships over 6 cohorts in its first phase, along with 58 students over 3 cohorts in its second phase.

The 120 projects available for application, are aligned to the following themes;

• Infection, Immunity, Antimicrobial Resistance and Repair

• Neuroscience and Mental Health

• Population Health Sciences

 

Applications open on 10th September 2024 and close at 5.00pm on 4th November 2024.

Studentships will be 4 years full time.  Part time study is also available.

Project Information

Research Theme:Infection, Immunity, Antimicrobial Resistance & Repair

Summary

Tuberculosis (TB) caused by Mycobacterium tuberculosis (Mtb) is a devastating infectious disease causing over one million human deaths every year. We urgently need new drugs/therapies to fight the accelerating problem of drug resistance in TB. Oxygenated sterols: oxysterols and oxygenated lipids: oxylipins are biologically important molecules in metabolism, infection and immunity and are emerging new targets for anti-TB drug development. However, the precise role of these molecules in infection is not clear. This project will investigate which oxysterols and oxylipins are important in TB and how they boost human host’s defence against the pathogen to provide new drug target

Description

Tuberculosis (TB) caused by Mycobacterium tuberculosis (Mtb) is a devastating infectious disease causing over one million human deaths every year. TB treatment is complicated by the rapidly rising cases of drug resistance and therefore, we urgently need new treatments to fight drug-resistance and stop TB.

Oxygenated sterols called “oxysterols” and oxygenated lipids called “oxylipins” are biologically important molecules that can be generated by the cytochrome P450 pathways and/or reactive oxygen species (ROS) autooxidation pathways. These biomolecules are important in infection and immune response against the pathogenic Mtb and are attractive targets for new therapeutic development. However, our knowledge about the role of these molecules in human host and Mtb, and host-pathogen interactions are not clear.

The lead supervisor’s research has demonstrated that the levels of oxysterols 25-hydroxycholesterol and 27-hydroxycholesterol are significantly reduced in the serum of patients with active pulmonary TB disease when compared to healthy individuals. In case of patients with extrapulmonary TB, the levels of these oxysterols are significantly elevated (~10-fold) when compared to the healthy individuals.

Therefore, oxysterols are reprogrammed in infected human host and are important and attractive targets for host-directed therapy. But further investigation is needed to establish the role of these oxysterols in Mtb and interactions with the host. Oxylipins are derived through oxygenation of lipids and important regulators of metabolism and immune signalling in multiple human diseases including cancer and neurodegenerative diseases. Oxysterols and oxylipins share common biosynthetic pathways involving P450 enzymes and ROS; but our knowledge of oxylipins in TB is very limited.

How oxysterols and oxylipins co-function? What are their roles in the host and pathogen? Are they cytotoxic or nutrients for Mtb? Do they boost metabolism and immune defence against Mtb? These questions will be investigated throughout the PhD project. The aim of the project is to profile oxysterols and oxylipins in the human host immune cells (macrophages) and Mtb and to investigate their roles in the metabolism of the host and pathogen. The outcomes from this research will enhance our knowledge of thesebiologically important molecules in TB and provide directions for new treatments/therapies.

The project is interdisciplinary involving TB biology, microbiology, molecular biology and protein biochemistry, analytical chemistry (metabolomics), metabolic modelling (involves computational approaches) and fluxomics (experimental and computational approach). The student leading this project will gain expertise in TB infection biology and mycobacteriology which can be applied to other mycobacterial diseases. In addition, the project will train the student in core skills including analytical mass spectrometry (method development and optimisations) and computational metabolic modelling that can be applied across various disciplines such as other pathogens, animals and plants.

Throughout the project, the student will be supported and guided by the supervisory team to write and publish first author publications, attend conferences to network and present his/her work. Beyond the PhD, the student will be ready to pursue a research career and future academic roles. The core skills gained in analytical chemistry and computational analyses will support the student to pursue a career in industry (example in drug discovery).

Specific objectives of the PhD programme:

(i) Profiling oxysterols and oxylipins in infected human macrophages and in Mtb using metabolomics and lipidomics to identify those molecules that are significantly reprogrammed in the host and the pathogen.

(ii) Identifying which oxysterols and oxylipins are used as nutrients by Mtb during infection using 13C-fluxomics to map host-pathogen interaction.

(iii) Investigation of the cytochrome P450 enzymes in Mtb involved in metabolism of host oxysterols and oxylipins and assessing their potential as drug targets.

Areas student can take ownership and steer the project:

Objective

(i) will involve metabolomics, lipidomics, method development and optimisation, where the student will be trained in core analytical skills of mass spectrometry. There are opportunities for the student to develop new methods and improvise existing methods of the supervisory team, steering the analytical analyses of the project.

Objective (ii) will provide the student with training in interdisciplinary skills in experimental and computational fluxomics that involves metabolic modelling. The student will have the opportunity to create new metabolic models for evaluating host-pathogen metabolic interactions. The student will identify multiple target fluxes and will assess “which” is/are the most important fluxes and steer the project to focus on important fluxes and pathways and streamline objective (iii).

Objective (iii) will train the student in structural biology and biochemical skills to investigate enzymes and proteins in Mtb. The student will have the opportunity to characterise new proteins and steer the project to focus on the target proteins for drug development.

Funding

This studentship is funded through GW4BioMed2 MRC Doctoral Training Partnership. It consists of UK tuition fees, as well as a Doctoral Stipend matching UK Research Council National Minimum (£19,237 p.a. for 2024/25, updated each year).

Additional research training and support funding of up to £5,000 per annum is also available.

Eligibility

Residency:

The GW4 BioMed2 MRC DTP studentships are available to UK and International applicants. Following Brexit, the UKRI now classifies EU students as international unless they have rights under the EU Settlement Scheme. The GW4 partners have agreed to cover the difference in costs between home and international tuition fees. This means that international candidates will not be expected to cover this cost and will be fully funded but need to be aware that they will be required to cover the cost of their student visa, healthcare surcharge and other costs of moving to the UK to do a PhD.  All studentships will be competitively awarded and there is a limit to the number of International students that we can accept into our programme (up to 30% cap across our partners per annum).

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 qualification gained outside the UK, in an appropriate area of medical sciences, computing, mathematics or the physical sciences.  Applicants with a lower second class will only be considered if they also have a Master’s degree. Please check the entry requirements of the home institution for each project of interest before completing an application. Academic qualifications are considered alongside significant relevant non-academic experience.

English requirements:

If English is not your first language you will need to meet the English language requirements of the university that will host your PhD by the start of the programme. Please refer to the details in the following web page for further information https://www.exeter.ac.uk/study/englishlanguagerequirements/

Data Protection

If you are applying for a place on a collaborative programme of doctoral training provided by Cardiff University and other universities, research organisations and/or partners please be aware that your personal data will be used and disclosed for the purposes set out below.

Your personal data will always be processed in accordance with the General Data Protection Regulations of 2018. Cardiff University (“University”) will remain a data controller for the personal data it holds, and other universities, research organisations and/or partners (“HEIs”) may also become data controllers for the relevant personal data they receive as a result of their participation in the collaborative programme of doctoral training (“Programme”).

Further Information

For an overview of the MRC GW4 BioMed programme please see the website www.gw4biomed.ac.uk

Entry requirements

Academic Requirements

Applicants for a studentship must have obtained, or be about to obtain, a first or upper second-class UK honours degree, or the equivalent qualification gained outside the UK, in an appropriate area of medical sciences, computing, mathematics or the physical sciences. Applicants with a lower second class will only be considered if they also have a Master’s degree. Please check the entry requirements of the home institution for each project of interest before completing an application. Academic qualifications are considered alongside significant relevant non-academic experience.

English Language Requirements

If English is not your first language you will need to meet the English language requirements of the university that will host your PhD by the start of the programme. Please refer to the relevant university website for further information.  This will be at least 6.5 in IELTS or an acceptable equivalent.  Please refer to the English Language requirements web page for further information.

How to apply

A list of all the projects and how to apply is available on the DTP’s website at gw4biomed.ac.uk.  You may apply for up to 2 projects and submit one application per candidate only.

Please complete an application to the GW4 BioMed2 MRC DTP for an ‘offer of funding’.  If successful, you will also need to make an application for an 'offer to study' to your chosen institution.

Please complete the online application form linked from our website by 5.00pm on Monday, 4th November 2024.  If you are shortlisted for interview, you will be notified from Friday, 20th December 2024.  Interviews will be held virtually on 23rd and 24th January 2025.

Further Information

For informal enquiries, please contact GW4BioMed@cardiff.ac.uk

For project related queries, please contact the respective supervisors listed on the project descriptions on our website.

Summary