The current research themes/projects being undertaken within the Centre for Paediatrics are:
I. Bone marrow failure/aplastic anaemia and related disorders
The principal research interest of Professor Inderjeet Dokal and Dr Tom Vulliamy is bone marrow failure focusing on the pathophysiology of the inherited bone marrow failure syndromes, particularly dyskeratosis congenita (DC). Research on DC has highlighted the important role of the enzyme telomerase in humans and the consequences of its dysfunction including dysregulated human development, premature ageing, increased risk of bone marrow failure and cancer. Current research is focused on elucidating the pathophysiology of the many uncharacterized cases of DC/aplastic anaemia as well as studies aimed at correction of the cell defect with the long term aim of developing new therapies for this group of patients.
II. Children’s environmental health and treatment of wheeze
Professor Jonathan Grigg’s environmental research is focused on our local population. The “Exhale” study is measuring changes in lung function and biomarkers of exposure to air pollution in primary school children over a 5 year period–coinciding with the introduction of the London low emission zone. Laboratory studies are assessing the mechanisms underlying the increased vulnerability to pneumococcal pneumonia in children exposed to particulate air pollution. In our NHS patients research is focused on treatment of preschool wheeze, difficult asthma and the prevalence of obstructive breathing in young children with sickle cell disease.
III. Developmental alterations in Down syndrome (DS)
Identifying molecular pathways altered by trisomy 21, leading to new insights into biology of Down syndrome (DS) is the long term research theme of Professor Dean Nizetic and Dr Jurgen Groet. This team identified the deregulation embryonic stem cell fate (Am J Hum Genet 2008, Mol Cell Proteomics 2009), and a new concept explaining how this de-regulation could be responsible for the increased leukaemia risk in DS children (Oncogene 2010). Work attracted media-attention including Press, live TV and Radio interviews, and support from the UK National DS Association (see http://news.bbc.co.uk/1/hi/health/7597761.stm). This team recently generated the first induced-pluripotency-stem-cells within the Blizard Institute (Figure 1), establishing a unique isogenic DS iPSC model. After co-coordinating a work package within the 12M€ EU-FP6- Integrated Project "AnEUploidy”, Professor Nizetic in 2011/12 got awarded 3 grants to model DS using iPSC: project grants from Kay Kendall Leukaemia Fund and the Jerome Lejeune Foundation, as well as a Strategic Funding Award from the Wellcome Trust as a part of a multi-disciplinary “LonDownS Consortium”, to tackle DS dementia and cognitive defect using iPSC modelling .
IV. Inherited myelodysplasia/leukaemia and cytopenias
In collaboration with colleagues (Drs Jamie Cavenagh, Banu Kaya and Paul Telfer) within Barts Health NHS Trust, studies are being undertaken on other haematological disorders; this includes the pathophysiology of inherited myelodysplasia/leukaemia (Professor Inderjeet Dokal and Dr Tom Vulliamy) and inherited cytopenias (Dr Paul Allen). Dr Paul Allen has expertise in analysis of the cell cycle and apoptosis and how these might be disrupted in human disease.
V. Neonatal medicine
The major emphasis of neonatal research has been the study of determinants of adverse outcomes following extremely preterm birth. This has involved long term collaborations between Professor Kate Costeloe and other institutions: the EPICure studies with Professor Marlow and studies of lung function with Professors Stocks and Dezateux. Other areas include the role of probiotics in prevention of complications of prematurity in collaboration with the Dept of Microbiology in Barts and the London, the use of Doppler ultrasound to study the neonatal circulation, particularly in relation to necrotizing enterocolitis (Dr Steve Kempley) and mechanisms of placental transfer of nutrients (Dr Shahid Husain).
VI. Paediatric infection and immunology
Dr Andrew Prendergast’s group has a focus on the interaction between infection, immunity and malnutrition, particularly in the context of HIV infection. Specifically, his group is investigating the role of microbial translocation, a pathological process that underlies two conditions of global public health importance: childhood malnutrition and HIV infection. Laboratory investigations of the causal pathway linking poor sanitation/hygiene and impaired growth in infancy and the link between the gut microbiota and growth are being explored. In parallel, the links between enteropathy and reduced immunogenicity of oral vaccinations and trialling interventions to improve vaccine efficacy in this setting is being investigated. Dr Prendergast’s group are also investigating the causes and consequences of chronic inflammation in HIV-infected children, focusing particularly on the role of coinfections (e.g. CMV and EBV), malnutrition and microbial translocation.