The Department of Paediatrics offers a range 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. Do have a read of our student testimonials too to find out more about what it is like to undertake a DPhil at the Department. 

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.

RE-ADMISSION CANDIDATES

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.

Target enrichment of transposable elements for direct RNA sequencing

Supervisors: Prof. Georg Hollaender, Dr Rebecca Berrens, (Commercial partner: Oxford Nanopore Technologies)

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.

Method:

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.

Aim:

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: caroline.hartley@paediatrics.ox.ac.uk

Applications by: TBC

Supervisors: Dr Yulia Lomonosova / Prof Matthew Wood (in collaboration with Tedesco lab, UCL)

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: yulia.lomonosova@paediatrics.ox.ac.uk