Prof C Harris, Dr D Newton
No more applications being accepted
Competition Funded PhD Project (European/UK Students Only)
About the Project
Paroxysmal nocturnal haemoglobinuria (PNH) is a haematological disorder characterised by clonal expansion of haematopoietic stem cells which cannot synthesise glycosylphosphatidylinositol (GPI) anchors (1). Daughter cells lack essential GPI-anchored complement control proteins and are therefore exquisitely sensitive to complement ‘tickover’ –a natural ongoing process which enables rapid response to infection. Patients develop thromboses, anaemia and become transfusion-dependent. Treatment of PNH was revolutionised in 2007 by the approval of an anti-C5 antibody, eculizumab, for therapy (2); this blocks the complement lytic ‘pore’ and prevents haemolysis. However, as C3 is activated prior to C5, C3-derived opsonins still accumulate on circulating E and cause extravascular haemolysis by binding complement receptors (CRs) on phagocytic cells, triggering erythrophagocytosis. This maintains a requirement for transfusion in a portion of patients and is purely a therapy-induced phenomenon as cells are no longer cleared by complement-mediated lysis (3). We have recently described the ‘complotype’ –an inherited pattern of complement gene variants which together influence the ability of complement to amplify and deposit C3 on targets and to be processed to different opsonins (4,5). We believe that a patient’s complotype can be used to identify patients which are at risk for extravascular haemolysis and who might benefit from targeted complement therapies which modulate C3-derived opsonins on the erythrocyte surface.
This project brings together an inter-disciplinary team of clinicians, geneticists, and complement experts and engages the two National Centres for complement mediated disease (in PNH, Leeds, and in renal disease, Newcastle). The successful candidate will assess PNH patients who are being treated with eculizumab (Hillmen) for their variation in complement genes (Kavanagh). Using bioinformatics, they will correlate patient complotype with a range of biological and clinical outcomes, including C3 deposition on erythrocytes (Harris, Newton), signs of complement activation in blood (Harris) and clinical parameters including need for transfusion (Newton). The work will result in a clinically invaluable prognostic tool, enabling risk stratification for extravascular haemolysis in PNH. The project will progress to early stage drug development by generating and testing cutting edge ‘homing’ drugs which will bind erythrocytes and modify the surface to prevent erythrophagocytosis (Harris). Suitable candidates are likely to have a background in biomedical sciences, biochemistry or biology with a keen interest in clinical science.
Funding Notes
DiMeN DTP studentships are funded for 3.5 years and include:
Tax-free maintenance grant set at the UK Research Council's national rate.
Full payment of tuition fees at the Home/EU rate.
A Research Training Support Grant to support your research studies.
Successful Home students will receive a full studentship. EU students will be considered for a full studentship/fees only support depending on the excellence of their qualifications and their employment/residency status.
Please carefully read the instructions on eligibility and how to apply at our website and use the link on the page to submit an application: http://www.dimen.org.uk/how-to-apply/application-overview
Application Website
http://www.dimen.org.uk/
References
1. http://mp.bmj.com/content/55/3/145.long
2. http://www.bloodjournal.org/content/bloodjournal/106/7/2559.full.pdf
3. http://www.bloodjournal.org/content/bloodjournal/113/17/4094.full.pdf
4. http://www.cell.com/trends/immunology/pdf/S1471-4906(12)00106-8.pdf
5. http://www.pnas.org/content/108/21/8761.full.pdf