Establishing a humanised zebrafish model for studying the genetic resilience in Neurofibromatosis Type 1 (NF1 MRC GW4 BioMed DTP PhD studentship for 2026/27 Entry, Department of Living Systems Institute Ref: 5623

Supervisors

Lead Supervisor:  Professor Steffen Scholpp - University of Exeter - Faculty of Health and Life Sciences

Co-Supervisors

Dr Toby Phesse - University of Cardiff

Professor Benjamin Housden - University of Exeter - Faculty of Health and Life Sciences

Dr Florian Siebzehnrubl - University of Cardiff

The GW4 BioMed2 MRC DTP is offering up to 17 funded studentships across a range of biomedical disciplines, with a start date of October 2026.

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 80 students over 4 cohorts in its second phase.

The 122 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 1 September 2025 and close at 5.00pm on 20th October 2025.

Please note that we may close the application process before the stated deadline if an unprecedented number of applications are received– check our website for details.

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

Project Information

Research Theme:  Infection, Immunity & Antimicrobial Repair

Summary:

This PhD project explores the phenomenon of "genetic resilience" in the context of Malignant Peripheral Nerve Sheath Tumours (MPNSTs), aggressive cancers linked to Neurofibromatosis Type 1 (NF1). Although individuals with NF1 are more likely to develop MPNSTs, the varying incidence indicates that certain cellular mechanisms provide protection against malignant transformation. This research seeks to uncover the molecular pathways behind this resilience and, therefore, identify new therapeutic targets that could boost cellular defences, opening new possibilities for prevention against MPNSTs. By using zebrafish as an in vivo model for NF1, this PhD project aims to investigate innovative strategies for disease prevention. 

Description:

Malignant Peripheral Nerve Sheath Tumours (MPNSTs) are highly aggressive and often fatal cancers, affecting about 10% of patients with Neurofibromatosis Type 1 (NF1). NF1 is a genetic disorder caused by mutations in the NF1 gene, which encodes neurofibromin, a vital negative regulator of Ras activity. While individuals with a single mutated NF1 copy are predisposed to tumour formation, the occurrence of MPNSTs is not universal. The progression from benign neurofibromas to MPNSTs typically involves additional mutations in key tumour suppressor genes such as TP53. Current treatment options for MPNSTs are very limited, with poor responses to chemotherapy and radiotherapy, and surgical removal is often unfeasible, resulting in a dismal 5-year survival rate of 20-50%. Since MPNSTs are classified as a rare cancer, affecting roughly 3 in 100,000 individuals worldwide, there is an urgent need for robust in vivo models to understand the fundamental biological pathways driving MPNST development and to aid in the discovery of new therapeutic interventions.

This PhD project aims to establish and thoroughly characterise a humanised zebrafish model for Neurofibromatosis Type 1, which will serve as a valuable tool to elucidate the biological pathways involved in MPNST progression and provide a platform for future drug screening efforts.

Objective 1: Establish and Characterise Humanised NF1 Zebrafish Models with MPNST-associated Mutations. This objective will focus on the generation and detailed characterisation of novel humanised zebrafish models that accurately reflect the genetic landscape of NF1 and MPNST. First, we will establish a humanised zebrafish model where the endogenous zebrafish nf1 genes are functionally replaced with the human NF1 gene. This will be achieved through advanced CRISPR/Cas9 editing to generate a stable nf1a/b background, followed by the introduction and stable integration of the human NF1 gene using a long knock-in construct. Within this humanised background, we will then employ an adapted prime editing strategy to precisely insert single- nucleotide variants or small indels that mimic identified human NF1

mutations, specifically focusing on notable missense mutations affecting codons 844-848 within the cysteine-serine-rich domain of NF1. Crucially, we will subsequently introduce a knockout of the TP53 (p53) gene in these humanised NF1 mutant backgrounds using CRISPR/Cas9, as TP53 mutations are frequently observed in MPNST progression. We will then perform single-cell sequencing on Schwann Cells from these NF1 mutant and NF1/TP53 double mutant "humanised MPNST-CRISPants" (CRISPR- induced MPNST-like zebrafish) at early developmental stages (e.g., 5dpf larvae) and in adult zebrafish (e.g., 3-month-old). This transcriptional analysis will allow us to characterise the molecular consequences of these specific genetic alterations in peripheral nerve sheath cells and identify key biological pathways perturbed during early MPNST development.

Objective 2: Functionally Analyse MPNST Progression in Humanised Zebrafish Models.

Using this zebrafish model, we will then focus on the functional characterisation of MPNST progression in vivo. We will phenotypically assess tumour formation and growth in the humanised NF1 mutant and NF1/TP53 double mutant zebrafish. This will involve detailed histological analysis, imaging techniques (e.g., fluorescence microscopy in Tg(sox10- GFP) background to visualise Schwann cells), and quantification of tumour incidence, size, and growth rate over time in both larvae and adult fish. Additionally, we will explore the cellular microenvironment and immune cell infiltration within developing tumours to gain a comprehensive understanding of the in vivo disease pathology. This objective will validate the humanised zebrafish model as a relevant system for studying MPNST biology.

Objective 3: Identify the Underlying Mechanism for Genetic Resilience in MPNST Progression.

This objective aims to utilise the established humanised zebrafish model to identify factors that influence MPNST progression, laying the foundation for therapeutic development. We will conduct pooled in vivo CRISPant screens in the humanised NF1/TP53 zebrafish models. This screen will target a curated gene library, including those identified as key players in the biological pathways described in Objective 1, to find specific gene knockouts that either speed up or slow down tumour development within the peripheral nerve sheath. This will uncover genetic dependencies that could be targeted for intervention. This objective will offer key insights into potential therapeutic targets and candidate compounds for future drug development.

Student Benefits and Skill Development.

This PhD studentship provides an excellent training opportunity for a highly motivated life sciences student. The student will gain extensive expertise in cutting-edge molecular biology techniques, including advanced CRISPR/Cas9 and prime editing for precise genetic manipulation in vivo. A key part of the project involves developing and using sophisticated humanised zebrafish models, offering invaluable hands-on experience in in vivo disease modelling—a highly sought-after skill in both academia and industry. The student will become proficient in high-throughput genomic techniques such as single-cell sequencing, along with the necessary computational and bioinformatics skills for analysing large datasets. The student will also develop critical thinking, experimental design, data interpretation, and scientific communication skills, preparing them for a successful career in biomedical research.

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 (£20.20780 p.a. for 2025/26, 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 for the University of Exeter 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/

Please check the relevant English Language requirements of the university that will host the PhD project.  

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 for the University of Exeter 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.

Please check the relevant English Language requirements of the university that will host the PhD project. 

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, 20th October 2025.  Please note that we may close the application process before the stated deadline if an unprecedented number of applications are received– check the DTP’s website for details and updates

If you are shortlisted for interview, you will be notified from Tuesday, 23rd December 2025.  Interviews will be held virtually on 27th and 28th January 2026.  

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