MRC Enterprise Studentship Programme 2018 (industrial CASE awards)
Four industrial CASE (iCASE) studentships are available for doctoral study at Oxford, to start in October 2018. Applications must be received by 12 noon (UK time) Monday 8 January 2018.
Each iCASE studentship is fully-funded for four years with a stipend of £20,000 p.a., all tuition fees paid, plus a research training support grant. The studentships will be based in the University as part of the Oxford-MRC Doctoral Training Partnership, and will also involve close collaboration with a commercial partner, including at least 3 months working at the company during the course of the D.Phil. project.
The four projects are:
1. Probing presynaptic regulators of dopamine to identify new opportunities for therapy in Parkinson’s disease (Lead supervisor Prof Stephanie Cragg, commercial partner Cerevance Ltd)
2. Computational methods for rapid structural modelling of antigen–antibody interactions to improve identification of antigen-specific antibodies from Ig-seq repertoire data (Lead supervisor Prof Charlotte Deane, commercial partner Kymab Ltd)
3. Development of enhanced soluble gamma delta T cell receptors (Lead supervisor Prof Paul Klenerman, commercial partner Immunocore Ltd)
4. Discovery and investigation of the genetic and mechanistic basis of β-cell fragility (Lead supervisor Prof John Todd, commercial partner Novo Nordisk)
Structure and organisation of the programme
Designed to nurture the academic entrepreneurs of the future, the Enterprise studentship programme offers a stimulating educational experience as part of the Oxford-MRC DTP cohort, with the additional benefit of working closely with a non-academic partner. This will provide industrial training opportunities and an insight into how commercial science is conducted alongside a superb academic base within the University.
Within equal opportunities principles and legislation, applications will be assessed in the light of an applicant’s ability to meet the following entry requirements:
1. Academic ability
Proven and potential academic excellence
Applicants are normally expected to be predicted or have achieved a first-class or strong upper second-class undergraduate degree with honours (or equivalent international qualifications), as a minimum, in a relevant discipline such as biology, biochemistry, or medicine. However, entrance is very competitive and most successful applicants have a first-class degree or the equivalent.
A previous master's degree is not required.
No Graduate Record Examination (GRE) or GMAT scores are sought.
Other appropriate indicators will include:
You will be required to supply supporting documents with your application, including references and an official transcript. See 'How to apply' for instructions on the documents you will need.
Performance at interview
Interviews are normally held as part of the admissions process.
Candidates who are shortlisted are interviewed as part of the admissions process. Shortlisting will be based on the criteria given above. There will be a minimum of two to three academics on the interview panel. By preference, interviews will be conducted in person, but when this is not possible we will use telephone or Skype (with video) and ensure that applicants are not disadvantaged by using these forms of communication. Normally the interview will consist of a five-minute presentation of previous project work by the applicant, followed by 15-25 minutes of questioning from the panel.
Prior publications are not required, but research experience and a track record demonstrating an interest in research may be an advantage.
Other qualifications, evidence of excellence and relevant experience
Evidence of a prior interest in the area of research proposed is likely to advantage your application.
2. English language requirement
Applicants whose first language is not English are usually required to provide evidence of proficiency in English at the standard level required by the University.
3. Disability, health conditions and specific learning difficulties
Students are selected for admission without regard to gender, marital or civil partnership status, disability, race, nationality, ethnic origin, religion or belief, sexual orientation, age or social background.
Decisions on admission are based solely on the individual academic merits of each candidate and the application of the entry requirements appropriate to the course.
Further information on how these matters are supported during the admissions process is available in our guidance for applicants with disabilities.
All recommendations to admit a student involve the judgment of at least two members of academic staff with relevant experience and expertise, and additionally must be approved by the Director of Graduate Studies or Admissions Committee (or equivalent departmental persons or bodies).
Admissions panels or committees will always include at least one member of academic staff who has undertaken appropriate training.
It would be expected that graduate applicants would be familiar with the recent published work of their proposed supervisor.
To be eligible for a full award, applicants must have no restrictions on how long they can stay in the UK and must have been ordinarily resident in the UK for at least 3 years prior to the start of the studentship. Further details about residence requirements may be obtained here.
How To Apply
Before applying for these positions we recommend you contact the lead supervisors for informal discussions. To make a formal application, please complete the University’s online application form for the DPhil in Clinical Medicine (course code RD_CM1). In your application, you must indicate that you are applying for an advertised studentship competition, using the reference code iCASE. Please indicate clearly which project(s) you are applying for, in order of preference. It is possible to apply for up to 3 MRC iCASE projects on your application. You will need to provide a CV outlining your academic achievements and relevant experience, and a personal statement (500 words max) detailing your interest and fit for the studentship. Note that no project proposal is required for the iCASE studentship applications.
If you wish to apply for a combination of iCASE and other projects within the administering department (the Nuffield Department of Clinical Medicine, NDM), this can be done on the same application form (3 projects max). If you wish to apply for both the iCASE projects and other projects in the Department of Physiology, Anatomy and Genetics (DPAG) and/or the Department of Statistics, you will have to make (an) separate application(s) directly through those departments in addition to your iCASE one.
If you have any specific queries about the iCASE application process, please email firstname.lastname@example.org. Advice on how to pick a graduate advisor and how to choose a scientific problem can be found in these two articles:
- Ben Barres, 2013, How to pick a graduate advisor, Neuron.
- Uri Alon, 2009, How to choose a good scientific problem, Mol Cell.
All applications must be received by the deadline of 12 noon (UK time) Monday 8 January 2018.
We expect to interview shortlisted applicants at the end of January and to make offers in February. Successful applicants will be rerouted onto the appropriate DPhil course for their chosen project.
Probing presynaptic regulators of dopamine to identify new opportunities for therapy in Parkinson’s disease
Parkinson’s disease is a progressive degenerative disorder, with debilitating movement problems that arise from the demise of nigrostriatal dopamine neurons and striatal dopamine transmission. Current strategies to restore dopamine are limited, and the mainstay of therapy, L-DOPA, has disabling side effects such as dyskinesias that prevent its long-term use. Therefore, there is a need to identify new treatments. Strategies are needed that can either slow disease progression, treat symptoms or treat side effects.
Nigrostriatal dopamine neurons have unique neurobiology. They have the most branched axonal arbours yet documented for CNS neurons. In turn, mechanisms located directly on dopamine axons powerfully regulate the striatal release of dopamine. New insights indicate that these mechanisms can critically determine dopamine release over and above activity in dopamine neuron soma. Axonal mechanisms might therefore offer novel and extensive opportunities for therapeutic benefit in Parkinson’s disease that are not currently being fully explored or exploited. This project will apply new and emerging technologies to explore dopamine axons as targets for new therapies.
In this project, we will explore and identify new strategies to govern dopamine transmission in striatum that could provide new potential targets for Parkinson’s therapy. We will use our expertise in methods to monitor dopamine transmission and neuronal activity in order to identify effects of underexplored neuromodulatory receptors that are present and also, of new and emerging candidate receptors and signalling pathways. To identify new candidate molecular mechanisms, we will exploit a powerful new technology platform at Cerevance for analysis of human dopamine neurons, alongside analysis of mouse dopamine neurons in transgenic models of Parkinson’s disease developed at the Oxford Parkinson’s Disease Centre. Targets will include those found to be enriched in human nigrostriatal neurons as well as those found to be modified in mouse dopamine neurons in PD models. We will identify the impact of these target mechanisms on dopamine synapse and neuron function in brain slices and in vivo,aided by pharmacological tools and by targeted manipulation of cell activity e.g. using optogenetics, and will have the opportunity to explore new pipeline ligands in development at Cerevance
The project capitalizes on the complementary strength and interests of Oxford and Cerevance in neurodegenerative research, and provides an opportunity to train a student in state-of-the-art skills in whole organism work and drug development.
Computational methods for rapid structural modelling of antigen–antibody interactions to improve identification of antigen-specific antibodies from Ig-seq repertoire data
The exquisite antigen recognition specificity of antibodies has made them useful as diagnostics, research agents and the most successful class of biopharmaceuticals. The ability to discover better antibody-based therapeutics needs knowledge of the sequence and the 3D shape of individual antibodies within the context of the entire antibody repertoire. Next-generation sequencing methodologies (Ig-seq) can rapidly yield millions of antibody gene sequences and have been used to identify antigen-specific sequences. However, so far the inability to routinely overlay antibody structure on large Ig-seq datasets has limited their potential for antibody drug discovery. Detailed structural information can be gained from low-throughput techniques such as X-ray crystallography, but these are not feasible to carry out on the scale of the entire repertoire. Computational methodologies offer a bridge between the two fields by allowing structural annotation of Ig-seq experiments.
The availability of antibody structures and maturity of modelling techniques, many of which have been developed by Professor Deane’s group, means it is now possible to perform large-scale structural characterizations of Ig-seq samples. This enriched structural content can be used to perform more precise characterization of antibodies, to allow inter-antibody comparisons, to facilitate grouping of structurally similar sequences (not obvious from sequence level data alone) and finally permit annotation of antibody developability information. Large scale Ig-seq datasets can also direct computational tools for targeted interrogation of antibody structural space. Statistical knowledge of the distribution of the antibody structures and sequences can offer crystallographers an idea of the common but currently unknown antibody variants. Therefore, the Ig-seq and structural world can benefit from cross-fertilization of ideas and methodologies which will advance our knowledge of the antibodies in health and disease and hence, pave the way for more advanced antibody- based therapeutics.
This project will combine expertise in i) investigating immune responses with Ig-seq and access to clinical samples for generating Ig-seq datasets (OVG) ii) the development and application of computational tools for modelling antibody structures and their docking with antigens (OPIG) and iii) access to unique data sets from large-scale well characterized monoclonal antibodies against a variety of therapeutic targets which can be used to optimize and validate the computational tools (Kymab Ltd).
Aims and approximate time-lines:
- Kymab antibody data will be used to improve computational methods for antigen– antibody docking and identification of 3D-structures for any antigen-antibody interaction using known antibody-antigen data sets (months 0-24)
- Structural computation analysis will then be applied to large-scale Ig-seq data from individuals exposed to the relevant antigens to identify novel-sequences predicted to bind antigens (months 12-24)
- Candidate antibodies will be confirmed using expression of up to 200 monoclonals which will be tested in standard assays at Kymab. The structural and experimental data from these experiments will be used to evaluate and refine the computational models (months 24-48).
A focus of the project will be Bordetella pertussis, Salmonella Typhi and Ebola virus as areas of common interest between Kymab Ltd and the Oxford Vaccine Group with samples from completed clinical trials providing Ig-seq samples for both antigens.
Development of enhanced soluble gamma delta T cell receptors
Gamma Delta T cells (γδ T cells) are an abundant human subset which “bridge” between innate and adaptive immunity. These cells show enrichment in mucosal tissues and infiltrate diverse types of tumours. Their activation occurs following T cell receptor (TCR) engagement or in response to pro-inflammatory cytokines. Stimulated γδ T cells are able to secrete a range of pro-inflammatory and anti-microbial cytokines, and also kill targets. Thus they are of potential interest in host defence and the therapy of cancer.
Vγ9Vδ2 cells are abundant in human blood and react to microbial molecules, such as HMBPP, or endogenous molecules accumulated in tumour cells, such as IPP, when bound to BTN3A1. Other populations of γδ T cells, which do not express the Vγ9Vδ2 TCR, exist in humans and are enriched in mucosal tissues. The molecular targets of these T cells are essentially unknown and their potential in control of tumours remains unclear.
This project aims to
- Generate soluble TCRs from Vγ9Vδ2 T cells for use in detection of BTN3A1 bound to microbial and tumour antigens. These TCRs will be modified through mutational approaches to enhance binding and sensitivity.
- Test these γδ TCRs as bispecific molecules in vitro to define their specificity and sensitivity
- Test these reagents using a new method (Chip Cytometry) to identify presentation of ligand in situ in bacterially infected cells and cancer tissues.
- Screen mucosa-derived and tumour-derived γδ T cell clones for novel TCRs and novel reactivities.
The student will work closely with Immunocore scientists to develop and test the new tools, and with University scientists to analyse their biologic roles and activity in tissues.
This project is aimed to address basic science questions regarding tumour immunity, and also to translate these for the improvement of human health.
Discovery and investigation of the genetic and mechanistic basis of β-cell fragility
The prevalences of type 1 (T1D) and type 2 diabetes (T2D) are still increasing, but their aetiologies were until recently thought to be entirely distinct: islet β-cell failure to produce sufficient insulin to compensate for insulin resistance in T2D versus autoimmune destruction of pancreatic islet β cells in T1D. However, the discovery that a polymorphism of the GLIS3 gene predisposes to both T1D and T2D, through altering β-cell sensitivity to stress, has highlighted β-cell health as a common denominator.
This project combines the unique strengths of the Todd in NDM - in studying the genetic and molecular causes of T1D and its genetic overlaps with T2D - and the NNRCO (Prof James Johnson) - in studying the cell biology of pancreatic β-cell survival and in implementing high-throughput screens and the latest imaging technology - to investigate the genetic and mechanistic bases underlying β-cell health and diabetes.
Our ongoing analyses show that >150 genes in over 60 T1D risk regions are expressed in β cells and that several T1D-candidate variants colocalise to regulatory motifs active specifically in human islets and not in immune cells. However, stress conditions, similar to those encountered in the pre-diabetic pancreas, are likely to alter chromatin states and gene regulation dramatically.
The proposed project has two parallel aims:
- Investigate how genes in several newly identified T1D regions (some of which overlap with T2D risk loci) cause diabetes through β-cell fragility.
- Discover new genes/pathways required for β-cell health by investigating the effects of stress and diabetes status on chromatin states and gene regulation in human donor islets.
Aim 1 will use gene knockdown approaches to screen through protein-coding genes proximal to regulatory regions active specifically in islets. We will compare effects in β cells (EndoC-βH1 cells assembled into spheroids/pseudoislets and donor islets) subjected to chemical (thapsigargin), immune (cytokine treatment, co-culture with cytotoxic T cells) and genetic (e.g. GLIS3 loss-of-function) stresses versus non-stressed conditions.
In aim 2 we will define the changes in chromatin states between stressed and non-stressed donor pancreatic islets to identify genes and regulatory regions that may otherwise appear to be quiescent in control islets, using ATAC-seq and RNA-seq. The recent miniaturisation of these methods will allow us to split the islets from one donor into several experimental groups. Integration of transcriptomics and proteomics data will enable the in silico assembly of the data into functional pathways. Depending on tissue availability, we aim to compare findings with those from diabetic versus non-diabetic donor islets.
NNRCO expertise in designing and implementing screens to assess gene function together with Prof Johnson’s rich track record in β-cell physiology will be vital for the success of this project. Throughout the project, priority will be given to genes encoding members of the secretome or receptor proteins, due to their accessibility as targets for protein-based treatment. Here too, NNRCO access to the Novo Nordisk protein production capabilities will allow for the rapid proof-of-concept testing of key hypotheses arising from this work.