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Award details

Investigating the role of DNA methylation in C9ORF72 Amyotrophic Lateral Sclerosis. MRC GW4 BioMed DTP PhD studentship 2023/24 Entry, PhD in Medical Studies. Ref: 4517

About the award

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The GW4 BioMed2 MRC DTP is offering up to 20 funded studentships across a range of biomedical disciplines, with a start date of October 2023

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, EU 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 it’s first phase., along with 20 students in it’s second phase.

The 84 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 2nd September 2022 and close at 5.00pm on 2nd November 2022.

Studentships will be 4 years full time or up to 8 years part-time.

Project Information

Supervisory Team

Dr Emma Dempster, Exeter.

Dr Akshay Bhinge, Living Systems Institute, Exeter

Prof Nicholas Allen, Biosciences, Cardiff

Location:

Summary

During this PhD you will use innovative molecular techniques to investigate a repeat expansion in the C9ORF72 gene, the most common genetic cause of Amyotrophic lateral sclerosis (ALS). Recent evidence indicates C9ORF72 is epigenetically modified in patient neurons and correlated with patient survival. Using CRISPR-cas9 gene editing and motor neuron cultures obtained from patient stem cells you will investigate the role epigenetic factors play in ALS progression.

Details

Amyotrophic lateral sclerosis (ALS) is a fatal incurable neurodegenerative condition characterized by loss of motor neurons (MNs) which leads to progressive muscle paralysis with average survival 2–5 years after diagnosis. A repeat expansion in the C9ORF72 gene (C9RE) is the most common genetic cause of ALS. Healthy individuals usually display around 2-3 repeats whereas >1000 repeats are commonly reported in ALS patients. Downstream molecular consequences of this repeat expansion include lower C9ORF72 gene expression, formation of toxic nuclear RNA foci and protein aggregates, together contributing to MN dysfunction and cell death. Epigenetic processes mediate the reversible regulation of genes and orchestrate a diverse range of critical neurobiological processes in the brain. DNA methylation is the most stable epigenetic modification and has been strongly implicated in the aetiology and progression of ALS neuropathology. In particular, DNA methylation is altered at C9RE and is associated with both repeat length and disease progression. Importantly, increased DNA methylation at C9RE is associated with, later age at death and decreased disease duration. It has also been correlated with transcriptional silencing of the C9ORF72 gene and decreased accumulation of toxic RNA foci suggesting that this DNA modification may have protective effects in repeat carriers and could be potentially modifiable. The aim of this PhD project is to decipher the relationship between C9RE DNA methylation, repeat length and motor neuron function. These investigations will provide deeper mechanistic insights into how C9RE methylation status contributes to MN function and will provide potential therapeutic avenues based on targeted epigenetic manipulations. ED and NA have independently optimised a novel approach that uses a catalytically dead Cas9 fused to methylation machinery, TET to perform targeted demethylation of C9RE and two effector domains KRAB and DNMT3A-3L for targeted methylation. The student will use these approaches to evaluate the functional and molecular changes that occur in C9RE patient iPSC-derived motor neurons after targeted epigenetic manipulation.

The main aims of the PhD project will be:

1, To perform a thorough review of the literature on the C9RE region and to use bioinformatics tools to mine our existing DNA methylation data sets on motor neurons and ALS patient samples to identify optimal targets within the locus. For example, targets could include the repeat itself and/or the proximal CpG Island.

2, Using the latest epigenetic editing tools to target the C9RE region in differing repeat length carriers and isogenic control derived iPSCs and differentiated motor neurons, this aspect of the project will be guided by ED and NA.

3, Investigate how manipulating C9RE methylation changes the transcriptional landscape of C9RE and isogenic control iPSC-derived motor neurons under the guidance of AB and ED. The DNA methylation status of the C9RE locus in response to the targeted editing will be evaluated using Oxford Nanopore Technologies (ONT) long-read sequencing employing adaptive sampling. This approach allows accurate detection of all base modifications including DNA methylation and generates reads >10Kb, enabling accurate repeat molecular characterization other methods cannot achieve. ONT RNA sequencing is quantifiable and allows the direct assessment of alternatively spliced transcripts.

4. MNs differentiated from different length C9RE ALS patient-derived iPSCs will be used to test the phenotypic effects of manipulation of the C9RE locus. Phenotypic assays will be performed on electrically active day 30 MNs. A wide range of assays can be chosen to evaluate the cellular consequences of altering the C9RE methylation status depending on the direction of the project. Including neuronal survival, morphological analysis, synapse formation and neuronal activity using Ca2+-signalling (guided by AB and NA).

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 (£17,688 p.a. for 2022/23, updated each year), a Research & Training Support Grant (RTSG) valued between £2-5k per year and a £300 annual travel and conference grant based on a 4 year, full-time studentship.

Part-time study is also available and these funding arrangements will be adjusted pro-rata for part-time studentships. Throughout the duration of the studentship, there will be opportunities to apply to the Flexible Funding Supplement for additional support to engage in high-cost training opportunities.

Eligibility

The GW4 BioMed2 MRC DTP studentships are available to UK and International applicants. Following Brexit, the UKRI now classifies EU students as international. The GW4 partners have all 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).

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”).

For further information regarding data protection for the Application Process and if you become a student on one of the Programmes please click here.

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 UK degree, or the equivalent qualification gained outside the UK, in an appropriate area of medical sciences, computing, mathematics or the physical sciences. 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. This will be at least 6.5 in IELTS or an acceptable equivalent. Please refer to the relevant university for further information. Please refer to the English Language requirements web page for further information.

How to apply

Applications open 2nd September and close at 17:00 on 2nd November 2022

To begin a GW4 BioMed MRC DTP studentship, applicants must secure an offer of funding from the DTP. 

Stage 1: Applying to the DTP for and Offer of Funding

1. Select your projects from the project descriptions available on this website. You may select up to two projects in your application.  If you are applying for the ICASE project you must choose this as your first choice project and is only open to UK citizens as indicated on the website.
2. Submit your application using this online form before 5 pm on Wednesday, 2nd November  2022.
3. Student shortlisting is conducted in a blind review of studentship applications by theme-specific panels. Up to 60 top candidates who emerge from this deliberation will be invited to interview.
4. Informal, virtual meetings will be arranged by the successfully shortlisted candidates with the lead supervisors of each project to which they have applied before the formal interview.
5. Formal interviews will occur virtually by theme-specific panels including representatives from each GW4 institution on 25-26 of January 2023.
6. Student selection for up to 20 funded studentships occurs after the formal interviews. Projects are allocated based on the rank of the successful candidates, therefore, it is not always possible to offer an applicant their first-choice project.
7. A clearing period will follow until approximately mid-March until all places have been offered and accepted. For this reason, it is not possible to provide immediate interview results to shortlisted applicants.

Stage 2: Applying to the lead institution for an Offer of Study

Once you have been offered a studentship with the GW4 BioMed MRC DTP, you will need to apply for an Offer of a Place at the home institution of your lead supervisor. Please note that each institution has different application processes.

Applicants for projects based at the University of Exeter should apply to the DTP first to secure an offer of funding. Once an offer of funding is issued by the DTP, you will receive more information on submitting a formal application to the relevant institution, guided by the DTP and local admin contacts.

Selection Criteria

Your online application forms will be evaluated against the following criteria:

Proven academic quality: normally evidenced by an excellent performance to first degree and/or Master’s level but may also be demonstrated by a record of relevant professional practice.

Research potential: evidenced through their supporting statement and supported by performance in research projects at first degree and/or Master’s level, or another form of dedicated preparation for research.

Personal motivation & commitment: evidenced through their supporting statement, by their enthusiasm for the project area and how they see it relating to their career goals.

Non-biomedical disciplines: In line with supporting interdisciplinary and quantitative skills, special consideration will be given by the interview panels to non-biomedical applicants. Such candidates should not feel the selection criteria are biased towards biomedical applicants as their unique skills will be taken into account.

Candidates selected to interview will be evaluated against the following criteria:

Critical thinking assessed via discussion of a student-selected piece of data

Fit with the project: The interview panel will evaluate the candidate’s aptitude and understanding of the key issues in the project, supported by feedback from informal meetings with the potential lead supervisor.

Personal commitment & motivation

Contacts

If you have any queries about the GW4 BioMed MRC DTP or about applying for an Offer of Funding, you can get in touch with the DTP Team by emailing GW4BioMed@cardiff.ac.uk.

If you have any questions about applying for an Offer to Study, you can get in touch with the administrative team at your home institution:

 

Summary

Application deadline:2nd November 2022
Value:Stipend matching UK Research Council National Minimum (£16,062p.a. for 2022/23, updated each year) plus UK/Home tuition fees
Duration of award:per year
Contact: PGR Admissions Office pgrenquiries@exeter.ac.uk