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The Department of Paediatrics offers a variety of doctoral opportunities across its research themes. Take a look at the outlines of prospective DPhil projects - and please get in touch with the relevant supervisor to discuss the details.

The role of developmental stage specific programmes in infant/childhood leukaemia

Supervisors: Professor Anindita Roy and Professor Thomas Milne (WIMM)

Project outline: There have been remarkable advances in the treatment of childhood leukaemia, however some subtypes, such as infant leukaemia (iALL) have high relapse rates and poor survival; and more effective therapeutic strategies are needed. Natural history and molecular studies indicate that all cases of iALL originate in utero, it is distinct from childhood ALL, and most are caused by a balanced translocation of the MLL gene. The identity of the target prenatal B progenitor cell(s) in iALL is unclear. We have recently defined unique prenatal B cell developmental pathways and a possible target cell for iALL. These cells display a distinct, ontogeny-related gene expression pattern that is not seen in adult type progenitors, and they share many features with iALL cells. This project will explore whether these specific gene expression programmes provide a permissive cellular context for prenatal B-progenitor leukemia initiation, especially iALL, and whether they can be modified to develop new approaches to treatment.

Contact details: anindita.roy@paediatrics.ox.ac.uk

Applications by: 10th Jan 2020

Further information: The focus of our lab is to understand the link between human prenatal haematopoiesis and the origin and biology of childhood leukaemia, in particular infant acute lymphoblastic leukaemia (ALL). Infant ALL invariably originates before birth and MLL gene rearrangement is often sufficient to cause leukaemic transformation without additional genetic abnormalities. Our research aims to identify and characterise the poorly understood target cell population responsible for in utero initiation of infant ALL. This approach will allow us to identify pathways that can be targeted for future therapies in infant ALL.

Please note that applications for this project can also be submitted through the CRUK Oxford Centre DPhil in Cancer Science Programme for clinical and non-clinical tracks http://www.cancercentre.ox.ac.uk/graduate-studies/dphil-in-cancer-science-programme/

 

 

Efficacy and correlates of protection with a new paratyphoid vaccine in a controlled human infection model

 Supervisor: Professor Andrew Pollard

The project will examine the potential efficacy of a new paratyphoid vaccine using a controlled human infection model. Human volunteers will be vaccinated with a new paratyphoid vaccine and then challenged with wild-type Salmonella Paratyphi by mouth in a bicarbonate solution. The volunteers will be closely monitored for 2 weeks, and treated either on developing infection or at 2 weeks if no infection is detected. We will examine antibody and cellular responses to ascertain the immune mechanisms associated with protection. The study will involve state-of-the-art cellular and serological techniques to provide new insights into immunity against this neglected disease.

Contact details: andrew.pollard@paediatrics.ox.ac.uk  

Applications by: 10th January 2020

Further information: The Oxford Vaccine Group is an interdisciplinary research environment with expertise form vaccine design and development through translation in to human studies, through phase 1-IV clinical evaluation and human challenge studies, and vaccine evaluation in the laboratory using state pf the art technology. Work on enteric fever is a major focus of the group with the aim of improving health among some of the most vulnerable populations through vaccine prevention of typhoid and paratyphoid.

Jin, C., Gibani MM, Moore M, Juel HB, Jones E, Meiring J, Harris V, Gardner J, Nebykova A, Kerridge SA, Hill J, Thomaides-Brears H, Blohmke CJ, Yu LM, Angus B and A. J. Pollard (2017). "Efficacy and immunogenicity of a Vi-tetanus toxoid conjugate vaccine in the prevention of typhoid fever using a controlled human infection model of Salmonella Typhi: a randomised controlled, phase 2b trial." Lancet 2017 Dec 2;390(10111):2472-2480

 

 

The impact of apnoea on brain activity in preterm infants

Supervisor: Dr Caroline Hartley

Project outline: 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. Brain activity drives brain development during the critical preterm period but the immediate impact of apnoeas on brain activity is not well understood. The aim of this project will be to characterise the relationship between apnoeas and brain activity in preterm infants, and how this changes with development. EEG (electroencephalography) and physiology will be recorded simultaneously, and signal processing approaches will be used and developed to fully characterise this relationship. This research will enhance our understanding of apnoeas, and ultimately seeks to improve outcomes for prematurely-born children.

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

Applications by: 10th January 2020

Further information: The focus of the lab is to understand the impact of physiological instability on brain development in premature infants. 1 in every 10 babies are born prematurely; understanding and mitigating the long-term impact of premature birth is important to improve the lives of these children. We develop novel methodologies with the aim to provide a greater understanding of infant brain development and derive tools which can be translated to the clinical setting.

 

 

Intestinal inflammation and primary immunodeficiency

Supervisor: Professor Holm Uhlig

Project outline: Inflammatory bowel diseases (IBD) are a complex group of disorders with genetic predisposition. A minority of patients harbour extremely rare generic variants associated with Mendelian disorders. Maladaptation of the intestinal host microbial cross-talk towards intestinal bacteria can result in inflammatory bowel disease. Intestinal macrophages are key in this process since these cells phagocytose and remove translocating bacteria under homeostatic conditions without causing inflammation, whereas monocytes and monocyte derived macrophages can be major contributors of inflammatory cytokines if tolerance is broken. A genetically informed mechanistic concept of IBD suggests that immunosuppressive and anti-cytokine strategies should be combined with reinstalling of antimicrobial activity to induce and/or maintain remission. This project aims to characterise intestinal macrophage differentiation  and antimicrobial activity in patients with Mendelian forms if intestinal inflammation. A functional genomic approach characterising the functional effects of rare variants via technologies such as  single cell sequencing, proteomics and in vitro infection models will allow to understand key aspects of defective autophagy and resulting hyperinflammatory responses in those patients.

Contact details: Holm.Uhlig@ndm.ox.ac.uk

Applications by: 10th January 2020

Further information: The focus of the lab is to understand rare genetic defects that affect key mechanisms of the intestinal barrier function. We aim to understand patients that develop intestinal inflammation due to Mendelian disorders as proof of concept and understand how those mechanisms can direct novel diagnostics and treatments as well as inform on more common forms of intestinal inflammation (Uhlig & Powrie Annual Review Immunology 2018).

 

An evidence-based approach for treatment decision in pre-symptomatic patients with spinal muscular atrophy

Supervisors: Professor Laurent Servais 

Project outline: There have been remarkable advances in the treatment of spinal muscular atrophy, with different approaches such as intrathecal antisens oligonucleotide, splicing modifiers, and gene therapy that are either approved, or on the road to approval. This has completely transformed the prognosis of spinal muscular atrophy type 1 from a fatal untreatable disease of babies to a treatable disease, which unfortunately remains associated with severe disability.  However, pre-symptomatic treatment has been demonstrated to be transformative, and most babies treated before the symptoms present so far with a normal development. This has given rise to several newborn screening programs across the world.

It remains unclear how to identify patients who should be treated, since spinal muscular atrophy presents with a large phenotype, including adult forms. It is widely accepted that patients with 2 or 3 copies of the pseudo-gene SMN2 should be treated, but treating or not treating since birth patients with 4 copies remains a matter of debate.

We have organised an international workshop with key opinion world leader to identify the best methodology to base the decision on evidence. The aim of this PhD is to conduct the research. This requires the standarisation of the SMN2 copy numbers quantification, and the collection of data of patients certified with 4 copies. It also includes the identification of additional genetic biomarkers through the in-depth analysis of outliers.

This study will directly lead to the improvement of patient care, by identifying patients who should benefit from innovative - but expensive and sometimes burdensome - treatments.

Contact detailslaurent.servais@paediatrics.ox.ac.uk

Applications by: 10th Jan 2020

Further information: The focus of our team is to help innovative therapies in the field of neuromuscular diseases to reach the patients' bedside as soon, and as efficiently, as possible. This incorporates the development of outcome measures, natural history studies, innovative trials designs, and identification of best responders.

In the field of spinal muscular atrophy, we have been instrumental in the conduct of clinical trials, and innovative outcome measures development and validation. We have developed one of the first genetic newborn screening that allowed so far to identify and to successfully treat 7 babies soon after birth and prevent the onset of symptoms.

 

DEVELOPMENT OF A NOVEL VACCINE TO PROTECT AGAINST PLAGUE: IMMUNE MECHANISMS OF IMMUNOGENICITY

 

Supervisor: Associate Professor Christine Rollier

 

Plague, caused by Yersinia pestis, is a highly contagious and virulent infectious disease. Since the 1980s, the number of human plague cases has increased in >25 countries. In 2013, The Center for Infectious Disease Research & Policy (CIDRAP) noted increased incidence since 2005 and plague is now considered a re-emerging infectious disease. We have developed novel vaccine candidates. The mechanism by which the antibodies block infection is not understood, and identifying this mechanism would support the clinical development of a novel vaccine.  The aim of this project is to identify the antibody functions which are associated with protection against infection, by identifying the functional antibody profile induced by the novel protective vaccine as compared with those induced by less protective vaccine formulations. Moreover, the contribution of other aspects of the immune response may correlate with the immunogenicity and efficacy of the vaccine.The project will comprise a system serology approach, use of mouse models as well as human immunology, and will also explore the contribution of cellular and innate immune responses induced by the vaccine candidates, and how the vaccine delivery affects the immunogenicity.

 

Contact details: christine.rollier@paediatrics.ox.ac.uk

 

Applications by: 10th January 2020

 

Further information: The preclinical novel vaccine development team within the Oxford Vaccine Group is involved in the creation, design, preclinical and early clinical studies of new and improved vaccines against bacterial diseases and infectious diseases affecting children and vulnerable populations. Our current research activities, funded by the Medical Research Council, Innovate UK, the Oxford Biomedical Research Centre, and other funders and charities, include vaccine development against caspular group B meningococcus, plague, Q fever, enteric fever and pertussis, using state of the art technology. Several of our projects involve creation of intellectual property prior to publishing.

 

Daniels-Treffandier H, de Nie K, Marsay L, Dold C, Sadarangani M, Reyes-Sandoval A, Langford PR, Wyllie D, Hill F, Pollard AJ, Rollier CS. Impact of Reducing Complement Inhibitor Binding on the Immunogenicity of Native Neisseria meningitidis Outer Membrane Vesicles. PLoS One. 2016 Feb 12;11(2):e0148840.