Supervisors

Lead Supervisor: Dr Vicki Gold, University of Exeter, Department of Biosciences

CO-Supervisor: Professor Ian Collinson, Univrsity of Bristol, Department of Biochemistry

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: Neuroscience & Mental Health

Project Summary: Mitochondria provide energy essential for life and are dependent on the delivery of proteins from the cytosol for their biogenesis, maintenance and regeneration. Defects in protein import affect cellular bioenergetics and thereby cause muscular, neurological and age-related degenerative diseases. In this project, the effects of defective protein import will be studied at both the cellular and protein structure level using state-of the-art methodologies including CRISPR-based genome editing of human cells for cryo-electron microscopy. The results will boost understanding of how mitochondrial protein import is essential for mitochondrial homeostasis and health, and how import failure relates to disease.

Project Description: 

Background: According to The Endosymbiotic Theory, mitochondria arose due to the intracellular enslavement of bacteria. During eukaryotic evolution, the mitochondrial genome was significantly reduced, leading to a dependence on cytosolic protein synthesis, protein targeting and import for >99% of mitochondrial proteins.

Mitochondrial protein import machinery in the outer and inner membranes evolved to facilitate mitochondrial biogenesis. The Translocase of the Outer Membrane (TOM) complex serves as the entry gate for most mitochondrial proteins, with pathways diverging depending on the protein’s destination. Mitochondrial dysfunction, a hallmark of neurodegeneration, is increasingly linked to protein import machinery malfunctions, with catastrophic effects on health (1). The Gold lab has developed methods to visualise protein import on mitochondria by cryo-electron tomography (cryoET) (2–4) and has investigated neurodegenerative-related mitochondrial changes using the same methodology (5).

In Alzheimer's disease, amyloid precursor protein (APP) accumulates within mitochondria, interacting with both outer and inner membrane protein import machinery (6). Similarly, mitochondria from Huntington's disease brains exhibit aggregation-prone Huntingtin protein (Htt) variants that inhibit import at the mitochondrial inner membrane (7). The Collinson lab has shown that a Tau protein associated with Alzheimer’s Disease interacts with the TOM complex (8), disrupting import and reducing neuronal complexity (e.g. less branching and fewer synapses).

Protein import is also crucial for mitochondrial quality control. In healthy cells, respiratory chain complexes of the mitochondrial inner membrane generate a membrane potential and ultimately production of ATP. A collaboration between the Gold and Collinson labs has revealed large scale structural changes in respiratory chain proteins in a model representing ageing and age-related neurodegenerative disease (9,10). In cells with a compromised membrane potential, the mitochondrial targeted kinase PINK1 accumulates at the TOM complex, where it is recognised by Parkin (9), which ultimately flags mitochondria for removal by mitophagy. Several PINK1 mutations are linked to early onset Parkinson’s Disease (11).

Whilst numerous studies have linked import dysfunction and impaired ATP production to neurodegenerative disease, the impact on mitochondrial ultrastructure and respiratory chain proteins remains unclear. Building on our existing collaboration, understanding the links between protein import and the structure and arrangement of respiratory chain proteins will provide further insight into the etiology of neurodegenerative diseases.

The key questions for this project are:
1. What is the consequence of mitochondrial import failure on the mitochondrial network, mitochondrial ultrastructure and respiratory chain protein structures?
2. How do these changes compare to mitochondrial abnormalities seen in various neurodegenerative diseases?

Objectives: We will work with established human cell culture that has been used as a model to measure the effects of import failure in the Collinson lab (12). Cells will be transfected and cultured using established conditions designed to perturb the protein import machinery (8,12).

This will include the expression of protein trapping constructs that arrest during protein import, as well as the production of aggregation prone proteins linked to neurodegeneration. Analysis of compromised HeLa cells by fluorescence microscopy revealed that both the protein trap and the aggregation-prone Tau caused similar effects, namely mitochondrial fragmentation (8,12). This studentship aims to advance the analysis of import-compromised HeLa cells by transitioning to structural cell biology, enabling a higher resolution examination of the impact on mitochondrial morphology. We will leverage use of brand-new technology that will shortly become available through a successful GW4 application to UKRI-BBSRC for a cryoFIB-SEM (1 of only a handful in the UK). Cryo-FIB milling of specimens that would otherwise be too thick to image by cryoET (e.g. cells and tissues) generates thin lamella suitable for subsequent imaging at high-resolution. The results will provide an extraordinary in situ view facilitating an investigation of the effects of import machinery perturbation on mitochondrial network formation, ultrastructure, and proteins of the respiratory chain.

This project offers outstanding opportunities for training within the MRC cross-cutting themes of data science, interdisciplinary skills and translation and innovation (strategic skills section).

Where the student can steer the project: The student can design translocation-arrested substrates to focus on an area of neurodegenerative disease according to interest. The team will support the student with ideas development regarding specific mutations or substrates to study. They can revisit this and design additional substrates as the project and their research evolves.

References:
1. Lin, M. et al. Nature (2006).
2. Gold, V. et al. Methods Mol Biol (2017).
3. Gold, V., et al. A. EMBO Rep (2017).
4. Gold, V. et al. Nat Commun (2014).
5. Stockburger, C. et al. J Alz Dis (2014).
6. Devi, L. et al. J Neurosci (2006)
7. Yano, H. et al. Nat Neurosci (2014).
8. Needs, H. I. et al. J Cell Sci (2023).
9. Knapp-Wilson, A. et al. J Cell Sci (2021).
10. Buzzard, E. et al. In preparation.
11. Valente, E. M. et al. Science (2004).
12. Needs, H. I. et al. Nat Commun (202

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