Research Degrees: DPhil in Paediatrics and MSc (by Research) in Paediatrics
The Department of Paediatrics offers a variety of doctoral opportunities across its research themes. Take a look at the outlines of prospective DPhil and MSc by Research projects - and please get in touch with the relevant supervisor to discuss the details before submitting an application. Prospective students may apply to one of these programmes with their own research proposal. Please make sure you contact your preferred supervisor for a discussion of your project before submitting your application.
About these courses
The Department has major interests in developmental immunology, infectious diseases of infancy and childhood, HIV infection and immune control, design, development and testing of vaccines, and in paediatric molecular genetics. Subject areas cover a large spectrum of paediatric medical, and scientific research.
Applications for entry in 2023-24 are now closed.
For enquiries, you can contact the Graduate Studies Officer: email@example.com
CLINICAL DPHIL AT OXFORD
A doctorate is an important step in any clinical academic career. At any one time, numerous doctors are undertaking a DPhil at Oxford.
For Oxford PGT students wishing to undertake a DPhil in Paediatrics.
YOUR CONTRACT WITH THE UNIVERSITY
Please read the following information on the main University pages carefully before accepting an offer from us.
Available DPhil projects for 2023
Target enrichment of transposable elements for direct RNA sequencing
In our conventional understanding, we often assume that all cells in our body possess the same genetic information. However, this is not entirely accurate, as only a small portion of our genome, approximately 2%, comprises protein-coding genes responsible for producing essential functional proteins. Astonishingly, the vast majority of our genome, around 50%, is composed of transposable elements (TEs), which are genetic entities capable of moving and rearranging their positions within the genome.
One particularly important class of transposable elements in humans is called LINE1 (Long Interspersed Nuclear Element 1). LINE1 elements constitute a substantial portion of our genome, accounting for approximately 17%. What sets LINE1 elements apart from other transposable elements is that they have retained their activity over evolutionary time, making them capable of moving around within the genome. As a result of this mobility, about 20% of new mutations in humans can be traced back to LINE1 insertions. Due to such mobility, LINE1 elements have been linked to the development of various congenital diseases, including hemophilia, Duchenne muscular dystrophy, and Dent disease.
Despite our knowledge of the DNA sequence of various LINE1 families, a critical piece of information remains elusive—the precise sequence of a retrotransposition-competent human LINE1 RNA. Retrotransposition refers to the process through which LINE1 elements move to new locations within the genome. Understanding this RNA sequence is of paramount importance for comprehending the role of LINE1 elements in congenital diseases. Therefore, the primary goal of this project is to directly sequence LINE1 RNA molecules, enabling the identification of the exact sequence and any RNA modifications present in a full-length human LINE1 molecule.
To achieve this ambitious goal, the project focuses on developing a target enrichment method for Nanopore direct RNA-sequencing. This methodology involves creating target enrichment probes designed to specifically capture and isolate the LINE1 RNA of interest. The target enrichment of LINE1 RNA will be done in human embryonic stem cells and human induced pluripotent stem cells, as these cells actively express LINE1 RNA. This project will be done in collaboration with Oxford Nanopore Technologies (ONT). ONT offers the unique possibility of direct RNA sequencing, a method that allows for the analysis of full-length RNA sequences. This technology also enables the mapping of RNA modifications on a single RNA molecule.
The key advantage of using LINE1 RNA for developing a new direct RNA-sequencing enrichment method lies in the fact that LINE1 insertions possess strikingly similar sequences at multiple sites within the genome. This sequence similarity allows for an efficient pulldown of LINE1 RNA using a process called hybridization, wherein the RNA is attracted to and bound by its own matching sequence. Once the target enrichment method is meticulously optimized, it can be applied to perform targeted sequencing of other significant genetic elements, such as single-copy genes or other transposable elements.
The goal is to understand the sequence composition of an active LINE1 RNA, to allow the development of small molecule inhibitors to prevent LINE1 de novo insertions that can lead to congenital diseases. These studies could pave our way toward the identification and treatment of diseases with genetic bases
Apply using course: DPhil in Paediatrics
THE IMPACT OF APNOEA ON BRAIN ACTIVITY IN PRETERM INFANTS
Supervisor: Dr Caroline Hartley
One in 13 babies are born prematurely; understanding and mitigating the long-term impact of premature birth is important to improve the lives of these children. Apnoea - the cessation of breathing - is a common pathology associated with prematurity. These potentially life-threatening events can result in reduced cerebral oxygenation and frequent apnoeas have been associated with long-term effects including reduced childhood cognitive ability. The focus of the research group is to understand the interaction between apnoea and brain development in premature infants, and to investigate how physiology is altered by pharmacological and non-pharmacological interventions. The group is part of a multidisciplinary team of clinicians, nurses, mathematicians, engineers and scientists. The group's work focuses on the collection and use of EEG (electroencephalography) and vital signs (heart rate, respiratory rate etc) data, and the group develops signal processing techniques and uses machine learning to derive tools with the aim to ultimately improve outcomes for prematurely-born children.
Contact details: firstname.lastname@example.org
Applications by: TBC
Discovering muscle-specific drugs employing human iPSC-derived 3D tissue-engineered muscles.
Neuromuscular diseases comprise a diverse group of mainly inherited conditions that typically affect striated muscles including the heart, resulting in progressive degeneration of these tissues and leading to very significant morbidity and mortality. These diseases are exemplified by Duchenne muscular dystrophy (DMD) which is a fatal inherited muscle disorder that arises due to defects in the dystrophin gene abolishing production of the dystrophin protein crucial for normal muscle and heart function.
Antisense oligonucleotides (ASOs) represent one of the fastest growing genetic based drug therapies for rare diseases. The major obstacle for developing ASO-based therapeutics is intracellular delivery of these drugs to skeletal muscle and heart to correct dystrophin gene. We are focusing on developing a targeted technology utilising cell-penetrating peptide (CPP) to deliver ASOs. However, CPPs have several drawbacks including low stability and tissue specificity. We will design chimeric CPPs exploiting computational biochemistry and bioinformatics approaches to improve the peptide stability, tissue specificity and endosomal release of ASOs. We will select novel CPPs possessing the potential to enhanced internalization based on utilisation of 3D artificial human skeletal muscle and heart, recapitulating the patient-specific features of the tissue structure in collaboration with Prof Saverio Tedesco, University College of London, London, UK). The platform technology and tissue-specific motifs can be highly relevant to other myopathies, neuromuscular disorders and inherited cardiomyopathies. Our lead CPPs will be repurposed via conjugation to alternative ASOs or different therapeutic cargoes to address wider applications e.g. targeting FOXO3 transcription factor in various pathological conditions including cardiovascular disease and cancer, which is also a part of this DPhil. Furthermore, proteolysis targeting chimeric (PROTAC) technology, a new class of drugs, will be applied to mediate selective ubiquitination and degradation of FOXO3. This work will involve a range of methodological techniques including but not limited to subcellular protein fractionation, phage display biopanning, atomic force microscopy, multi-omics analysis, computational biochemistry, high-resolution fluorescence microscopy.
The Wood lab is a multidisciplinary centre of excellence within the Department, MDUK Oxford Neuromuscular Centre and Oxford Harrington Rare Disease Centre, providing a superb environment for interdisciplinary molecular and cellular science. The laboratory has many collaborations with industry including with two recent spin-out companies. The Wood group possesses a whole spectrum of resources required for the project to be successful and is housed in a new regenerative medicine institute in Oxford, the Institute of Developmental and Regenerative Medicine (IDRM) (ox.ac.uk), with access to state of the art capabilities for drug development.
Contact details: email@example.com
Example DPhil Projects
EXPLORING THE EARLY RESPONSE TO (PARA)TYPHOID EXPOSURE IN A HUMAN CHALLENGE MODEL OF INFECTION
Student name: Amber Barton
Supervisors: Professor Andrew Pollard, Dr Jennifer Hill and Dr Irina Mohorianu
Description: Several plasma cytokines have been found to transiently increase around 12 hours after healthy volunteers are experimentally exposed to Salmonella Typhi, regardless of whether they go on to develop signs of infection. This raises a number of questions, including the identity and location of the cells producing these cytokines, whether we can detect other immunological signatures of exposure, and whether such signatures differ between those who become infected and those who remain well. In this project these questions are being addressed using whole blood transcriptional analysis. Early differences in the transcriptome between individuals who remain well and those who develop disease have indicated genes which might be involved in protection. Furthermore, gene set enrichment analysis of blood transcriptional changes occurring 12 h post-exposure has allowed characterisation of early cellular responses, the significance of which is being investigated further with in vitro experiments.
Source of funding: St Cross Paediatrics Scholarship (Department of Paediatrics and St Cross College), with project support from Wellcome Trust and the Bill and Melinda Gates Foundation.
RAPAED-TB: EVALUATION OF NEW DIAGNOSTICS IN CHILDHOOD TB
Student name: Laura Olbrich
Description: Globally, children account for an estimated one million TB cases and more then 200,000 deaths due to TB per year. The main challenge is adequate and timely diagnosis as currently available diagnostic tests fail to diagnose the majority of children with TB. New testing strategies are therefore urgently needed. In a prospective, multi-country clinical study in four African countries and in India, diagnostic performance data on a number of promising novel assays and sampling strategies will be generated. In addition, the study will derive diagnostic and screening algorithms for TB using existing and these novel tests.
Source of funding: EDCTP
EVALUATING THE EFFECT OF IMMUNISATION WITH CAPSULAR GROUP B MENINGOCOCCAL VACCINES ON MENINGOCOCCAL CARRIAGE
Student name: Jeremy Carr
Supervisors: Dr Matthew Snape; Professor Martin Maiden
Description: Capsular group B meningococcal (MenB) vaccines provide direct protection against invasive MenB disease, however the effect on herd protection is not known. This study will evaluate the influence of MenB immunisation on oropharyngeal carriage in teenagers, and consequently the potential for these vaccines to disrupt transmission and provide broad community protection against MenB disease. Given the potential for immunisation with the subcapsular protein antigens in MenB vaccines to impact on the carriage of non-MenB pathogenic and commensal Neisseria species, carriage rates of these organisms will also be evaluated. Understanding the influence of MenB protein-based vaccines on herd protection will inform current vaccine policy and future vaccine development.
Source of funding: University of Oxford; Clarendon Scholarship; National Institute for Health Research; Department of Health.
ASSESSING THE IMMUNE MECHANISMS UNDERLYING THE IMMUNOGENICITY TO MENINGOCOCCAL GROUP B VACCINES
Student name: Dylan Sheerin
Description: The Gram-negative bacterium Neisseria meningitidis is the causative agent of invasive meningococcal disease (IMD), a severe bacterial infection which occurs predominantly in infants within the first years of life. Two meningococcus group B (MenB) vaccines have been licensed, but both have significant drawbacks. A novel MenB vaccine has been developed at the Oxford Vaccine Group, based on a viral vector. The vaccine candidate induced strong and persistent protective immune responses in mice after a single dose, and a phase I trial to assess its safety and immunogenicity in healthy adults is ongoing. The D.Phil student is working on understanding the mechanisms which underlie the responses induced by these distinct vaccines at the genetic, cellular and systems level, and the results will contribute to the rational design of future vaccine candidates for MenB and other bacterial diseases.
Source of funding: Medical Research Council
Further information: Currently in second year.