Supervisors

Lead supervisor-Dr Raquel Revuelta Iniesta, University of Exeter, Department of Medicine

Co-supervisor:

Professor Francis Stephens, University of Exeter, Department of Medicine

Professor Benjamin Wall, University of Exeter, Department of Medicine

Dr Marlou Dirks, University of Exeter, Department of Health and Sports Science

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:

Population Health Sciences

Summary

Survivors of childhood acute lymphoblastic leukaemia (ALL) experience premature frailty and muscle atrophy. Muscle protein synthesis is crucial for muscle growth and is mainly stimulated by physical activity and dietary protein. Since dietary protein intakes in ALL survivors do not differ from the general population, it is suggested that the observed muscle atrophy is caused by an inability of muscle growth to respond normally to dietary stimuli, termed anabolic resistance. This PhD will mechanistically explore if anabolic resistance underlies frailty in ALL survivors in response to diet, and design tailored dietary and exercise interventions to promote muscle growth.

Project description

Sixty percent childhood Acute Lymphoblastic Leukaemia (ALL) survivors experience frailty 25 years before the general population (44 vs. 69 years) (Smitherman et al. 2020). Frailty, defined as muscle atrophy, exhaustion/low energy expenditure and weakness (Fried et al. 2001), leads to more comorbidities, relapse, and death (Ness et al 2013). Skeletal muscle mass is determined by the balance of protein muscle synthesis (MPS) and breakdown. MPS is stimulated by exercise and dietary protein and is considered a predominant component that dictates muscle growth (Davies et al. 2020). Protein intakes in ALL survivors do not differ from the general population (Belle et al 2017) suggesting an inability of MPS to respond normally to dietary stimuli, termed anabolic resistance. Indeed, anabolic resistance is a primary driver for muscle loss with age and inflammatory conditions. We showed that anabolic resistance may be driving muscle loss in Crohn’s disease, which has a similar muscle phenotype to ALL (Davies et al 2021). Studies investigating if anabolic resistance is a pathophysiology mechanism of frailty and dietary strategies designed to ameliorate frailty in ALL survivors are lacking. This project will measure muscle protein balance in childhood ALL survivors and matched-healthy controls in the fasted and fed states together with inflammatory and functional readouts to provide holistic muscle phenotypes. The results will be used by the PhD student to devise and test various nutrition (e.g. protein) or exercise strategies to promote MPS in subsequent studies.

Key research questions
1. In those with muscle atrophy, is this explained by anabolic resistance of muscle in response to a protein-based drink in childhood ALL survivors when compared to matched healthy controls?
2. Do childhood ALL survivors have higher inflammation than matched healthy controls and is it associated with anabolic resistance?
3. Is higher protein intake associated with an improved forearm muscle protein net balance under fasted and fed conditions in both groups?
4. Can diet and resistance exercise overcome anabolic resistance in childhood ALL survivors?

Specific Objectives and PhD timelines:
Year 1, 9 months: Compare frailty phenotypes (body composition, muscle function and inflammation) in childhood ALL survivors and matched healthy controls.                                                                                                       Year 1, 12 months: Compare forearm muscle protein net balance under fasted and fed conditions in both groups. Explore associations between dietary patterns and inflammation and muscle net balance under fasted and fed conditions.                                                                                                                                                              Year 2 and 3: The student will devise and test various nutrition (e.g.protein) or exercise strategies in similar subsequent studies based on findings from the proposed study described below: Experimental Approach Cross-sectional study.

Population
There are 1200 ALL survivors in Southwest England. We will recruit 16 who have been cured for ≥5 years since diagnosis between the ages of 18 – 70 years and 16 age-, sex- and BMI matched healthy controls using social media.

We will exclude pregnant and lactating women and people with metabolic, severe cognitive and relevant allergy and intolerances. Protocol (Arterialised venous deep blood (AV-V)) (Dirks et al. 2019). Visit 1 takes 2.5 hours. We will measure body composition (BodPod), skeletal muscle strength, function, and balance, and ask participants to
complete a Food Frequency Questionnaire (EPIC-Norfolk) and physical activity (IPAQ). A standard meal will be provided to consume that night. Visit 2 is the experimental protocol, named AV-V performed in Nutrition
Physiology Research Unit by a very experienced research team. The experiment takes 5 hours structured in minutes as -60, 0 (Ensure Plus, Abbott Nutrition), +60, +120 & +180 min. Participants will be fasted and asked to rest on a bed for the experiment. Time -60 min: a 1st cannula will be placed into a dorsal hand vein and then in a heated hand warmer (55°C) for the remainder test day to repeatedly sample AV-V.

Time -60 min: a 2nd cannula will be placed into a deep-lying antecubital arm vein. Ultrasound is used to locate its anatomy, assist in the cannulation and calculate brachial-artery blood flow. These cannulas are kept patent by a continuous saline drip. Oxygen saturation confirms AVV blood.

Arterialised blood and venous blood samples will be collected at baseline (-15 min) every 15 minutes until +180 minutes (total 11 samples) to analyse insulin, glucose and serum branched chain amino acid concentrations. Brachial arterial blood flow will be assessed concurrently with blood sampling to calculate arteriovenous forearm balance of the measured nutrients. Inflammatory markers will be analysed from baseline samples. Resting and fed energy expenditure will be measured via indirect calorimetry at times – 30, +50 & -170 min.

Power calculation
A 2-sided ANOVA repeated measures power-analysis showed that the project requires 7 participants per group to detect differences in amino acid balance (µmol/min/100g forearm-lean-mass) between groups (α=0.05; 80% power). Two age groups (18 – 39 and 40 – 70) will account for the 25 years-age difference in frailty onset requiring 7x4 (28) with 10% drop-out (n = 32).

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