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A 3 year PhD studentship, which is funded by the charity Children with Cancer, is offered at Bristol University under the joint supervision of Dr Patrick Case (School of Clinical Sciences) Dr Jon Lane (School of Biochemistry) and Dr Allison Blair (School of Cellular and Molecular Medicine). The PhD student will explore a novel mechanism which might explain the aetiology of childhood leukaemia.
In two papers published in Nature Nanotechnology Drs Case and Lane have discovered that human cells may undergo DNA damage if they are exposed to signals that are released from the placenta after oxidative stress.
The student will test whether these signals from human placenta can cause DNA damage and chromosome aberrations in human fetal blood cells and whether this damage is similar to that observed in childhood leukaemia. They will test at which stage of development the blood cells might be damaged and whether damage leads to altered cellular function of the kind that is associated with leukaemia. They will explore whether altering a naturally protective mechanism in cells (autophagy) could influence this process, thereby allowing a new concept towards therapy.
Acute leukaemia is a consequence of malignant transformation of a haemopoetic progenitor cell. The development of childhood B-cell lineage acute lymphoblastic leukemia (ALL) involves (at least) 2 genetic events (hits), the first of which frequently arises prenatally. According to current models, a preleukaemic stem cell clone is generated by a first mutation in utero, which, in a minority of children, progresses to leukaemia after receiving further postnatal genetic hits. The nature of pre- and postnatal events involved in leukaemogenesis in children is not well understood. Although genetic predisposition and specific environmental exposures may account for individual cases, the bulk of childhood leukaemia cannot be explained by any of these factors. We hypothesise that agents, that cause oxidative stress (e.g. chemicals, diseases or altered oxygen tension (i.e. maternal bleeding)) could do so in the placenta and that this may cause DNA damaging signaling from the placenta to the fetus, particularly during early pregnancy when the barrier is bilayered. We suggest that this process could result in DNA damage in fetal blood cells and that could contribute to a first hit towards childhood leukaemia.
The student will receive all training necessary and will be exposed to all techniques within the three labs. They will learn modern cytogenetics, assays of DNA damage, fluorescence and confocal microscopy with live cell imaging, tissue culture of placenta, stem cells, cord blood and lymphoid cells and molecular biology. The Studenstship is available either now or in the autumn.
Interested candidates should contact and send cvs to
Patrick Case c.p.case@bristol.ac.uk, Jon Lane Jon.Lane@bristol.ac.uk, Allison Blair Allison.Blair@bristol.ac.uk
Funding Notes:
In November 1986, Paul O’Gorman was diagnosed with leukaemia.
He died just nine weeks later, aged fourteen years old.
Before his death, Paul’s parents promised to help other children with leukaemia, so no other child would have their life cut short by this dreadful disease.
Children with Cancer aims are to determine the causes, find cures and provide care for children with cancer.
They fund life-saving research into the causes, prevention and treatment of childhood leukaemia and other childhood cancers, and work to protect young lives through essential welfare and campaigning programmes.
References:
Bhabra G, et al Lane J, Case CP. Nanoparticles can cause DNA damage across a cellular barrier.Nature Nanotechnol.;4:876-83 (2009).
Sood, et al C.P. Case Signalling of DNA damage and cytokines across cell barriers exposed to nanoparticles depends on barrier thickness Nature Nanotechnology 6, 824–833 (2011)