The epigenetics of Parkinson’s disease: searching for novel drug targets. PhD in Medical Studies (MRC GW4 BioMed DTP) Ref: 3647
About the award
Dr Anna Migdalska-Richards, Institute of Clinical Biosciences College of Medicine and Health, University of Exeter
Prof Jonathan Mill, College of Medicine and Health, University of Exeter
Prof Nigel Williams, School of Medicine, Cardiff University
Parkinson’s disease (PD) is the most common human motor disorder, affecting ten million people worldwide. With an increasingly ageing population, prevalence is predicted to double by 2030. Parkinson's significantly contributes to the global burden of disease, costing the NHS alone more than £1 billion/year. Currently, there are no treatments that can cure or modify the disease, so development of new therapies that can slow, prevent or reverse PD progression are urgently required. Although some genetic components of Parkinson’s disease have been identified, much is still unknown about the aetiology. For example, the most common genetic risk factor (GBA1), which accounts for ~85% of all known genetic cases, shows incomplete penetrance, with only 30% of GBA1-mutation carriers developing the disease. Further, PD concordance rate between identical twins is only about 17%.
This indicates that non-DNA-sequence variation (i.e. epigenetics) plays a crucial role. In particular, recent work (including our own) shows that DNA methylation (the most well-studied epigenetic mark) is altered in the brains of people with Parkinson’s disease. It is now believed that future progress can only be made by understanding both the genetics and epigenetics of PD.
It is well-known that PD pathology differs both between brain regions and cell types. However, despite this, all previous studies of DNA methylation in PD brains have only analysed bulk brain tissue. This is a substantial drawback since results then include a mixture of cell types, each with their own epigenetic profile. This will mask the individual PD signatures from distinct cell types, and so hamper both mechanistic understanding and the search for novel drug treatments.
Supported by a recent £100k Wellcome Trust Seed Award, this project will directly address this problem by, for the first time, determining the role of DNA methylation in Parkinson’s disease separately in neurons, oligodendrocytes, and other glial cells. This has only recently become possible due to development of the method for separating cell-specific nuclei.
In addition, this project will (also for the first time) stratify individuals based on genetics. This will include both genome-wide SNP profiling and targeted gene sequencing, focussing on the GBA1 gene, but also including other PD risk genes such as SNCA, LRRK2, PRKN and PINK1. The hope is that this approach will lead to a step change in PD research, resulting in new mechanistic understanding and putative novel drug targets.
During this project, the student will learn a broad range of experimental and theoretical skills, including purification of neural nuclei, FACS sorting, DNA methylation profiling, genetic profiling and bioinformatics analyses. Although mainly based at the University of Exeter, six months will be spent investigating the genetic aspects of this project at the University of Cardiff in the group of Professor Nigel Williams.
Further, through collaboration with Dr Ryan Ames at the Living Systems Institute, the student will have the opportunity to develop basic computational network modelling skills in order to analyse genetic-epigenetic interactions. In addition, via collaboration with Professor David Collier, the student’s training will be further enhanced by regular visits to Eli Lilly for industrial experience, training and participation in seminars/courses. Finally, public involvement will play an important part of this PhD. This will build on existing links that we have recently developed with local Parkinson’s support groups, particularly those in Okehampton, Crediton and Exmouth. The student will participate in a number of public workshops, where they will be able to explain their work and interact directly with individuals affected by Parkinson’s disease.
This studentship is funded through GW4 BioMed MRC Doctoral Training Partnership. It consists of full UK/EU tuition fees, as well as a Doctoral Stipend matching UK Research Council National Minimum (£15,009 for 2019/20, updated each year) for 3.5 years.
For further information relating to the funding please see the main MRC GW4 BioMed website
This project is in competition with a number of other projects across the partnership; up to 18 studentships in total will be available.
Eligibility and Residency Requirements
To be eligible for a full award (fees and stipend) from a Research Council, a UK or EU student must have no restrictions on how long they can stay in the UK and have been ordinarily resident in the UK for at least 3 years prior to the start of the studentship.
An EU student who has not been resident in the UK for at least 3 years prior to the start of the studentship is generally eligible for a fees-only award from the Research Council: to be eligible for a fees-only award, a student must be ordinarily resident in a member state of the EU; in the same way as UK students must be ordinarily resident in the UK.
For our regular recruiting round, the Doctoral Training Partnership has additional funding from the partner universities to support a limited number of EU students who do not meet the UK residency requirements, so long as they meet the criteria for a fees-only award: these studentship will therefore be fully funded (fees and stipend).
For full details on eligibility, please refer to the MRC GW4 BioMed website
Students with 'International' status are unfortunately not eligible to apply.
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
For an overview of the MRC GW4 BioMed progamme, please see the website www.gw4biomed.ac.uk
In addition to those with traditional biomedical or psychology backgrounds, the DTP welcomes students from non-medical backgrounds, especially in areas of computing, mathematics and the physical sciences, and can fund additional training, including Masters to assist discipline conversion. Applicants for a studentship must have obtained, or be about to obtain, a First or Upper Second Class UK Honours degree, or the equivalent qualifications gained outside the UK, in an area appropriate to the skills requirements of the project. Applicants with a Lower Second Class degree will be considered if they also have a Master’s degree or have significant relevant non-academic experience.
If English is not your first language you will need to have achieved at least 6.5 in IELTS (and no less than 6.5 in any section) by the start of the programme.
How to apply
Applications Open on 29 September and close at 17:00 on Monday 25 November 2019
You will need to complete an application to the GW4 BioMed MRC DTP for an 'offer of funding'
Applying for an 'offer of funding'
Please complete the application form at https://www.gw4biomed.ac.uk/doctoral-students/ by 5pm Monday 25 November 2019.
The Research Theme Panels will complete the shortlisting and will aim to inform applicants by Thursday, 19 December 2019. If you are shortlisted you will need to:
- contact the lead supervisor of you chosen project in which you are interested, to arrange an informal interview (which can be in person, by telephone or by Skype) between 3 and 15 January 2020. Please note that interview expenses will not be available for candidates to attend these meetings.
- attend a formal interview, with a panel of four academics which will take place in Cardiff on 21 and 22 January 2020.
For further details of the application process please see the following web page www.gw4biomed.ac.uk/doctoral-students/
You do NOT need to apply to the University of Exeter at this stage - only those applicants who are successful in obtaining an offer of funding from the DTP will be required to submit an application to study at Exeter.
|Application deadline:||25th November 2019|
|Value:||Stipend matching UK Research Council National Minimum (£15,009 p.a. for 2019/20, updated each year) plus UK/EU tuition fees|
|Duration of award:||per year|
|Contact: PGR Recruitmentfirstname.lastname@example.org|