Idiopathic myelofibrosis (IMF) is a chronic pre-leukaemic condition characterised by fibrous scar tissue in the bone marrow which prevents normal blood stem cell function and impaired blood cell formation. Over 1,500 individuals are diagnosed with IMF in the UK each year, and the disease is associated with significantly impaired quality of life and a high risk of transformation to a treatment-resistant acute leukaemia.
My laboratory has a long-standing interest in understanding the biology of and developing therapeutics for IMF (Cell Reports 13:2345; Blood 131:782; Blood Adv 5:1922). We have uncovered that megakaryocytes in IMF patients undergo a process of growth arrest and senescence due to an inability to respond to DNA damage stress, a process which prompts the senescent megakaryocytes (sMKs) to release a panoply of pro-inflammatory cytokines that act on neighbouring stromal cells in the bone marrow to overproduce collagen and form fibrous scar tissue. For this PhD studentship, the student will have the opportunity to engage with academic, industrial and clinical partners to extend on this work and to discover new therapeutics for this fatal disorder:
1) The student will seek to understand the molecular mechanisms governing megakaryocyte senescence, by analysing clinical bone marrow aspirates from IMF patients by NanoString technology, an exciting sequencing platform which can quantify thousands of gene expression changes directly on tissue sections. The student will also apply CRISPR-based approaches to functionally validate gene targets as important contributors to megakaryocyte senescence.
2) The student will generate a novel, physiologically-relevant 3D co-culture model of the IMF bone marrow by recapitulating the cell-cell interactions between sMKs and stromal elements within the bone marrow. By working with academic collaborators in London, the student will learn to synthesise biocompatible polyester scaffolds that mimick the mechanical properties and porosity of bone, and use these structures to support co-cultures with in vitro-derived sMKs and mesenchymal stromal cells to re-create an IMF microenvironment. The student will further learn to analyse bone marrow architecture, fibrotic phenotypes and cytokine profiles using various bioimaging and molecular assays.
3) Finally, the student will leverage the IMF bone marrow 3D co-culture to test a panel of pharmacological or gene-based therapies to target the sMK population and assess for amelioration of the pro-inflammatory cytokine signature and fibrotic phenotype. This could lead to the identification of novel therapeutics for the treatment of IMF.
The studentship will be based in the John van Geest Cancer Research Centre, and provides a unique opportunity to develop core experimental skills in biochemistry, cell biology and fluorescence microscopy, facilitated by the supervisory team and the excellent research facilities available at the University. Dr. Edwin Chen, Professor Sergio Rutella and Dr. Jehan El-Jawhari are all members of the Cancer Biology, immunology and therapeutics team within the Centre for Health, Ageing and Understanding Disease (CHAUD) at Nottingham Trent University, which encourages multidisciplinary research and has a diverse and supportive postgraduate community.
Further information on the project and how to apply can be found on our website: https://www.ntu.ac.uk/research/find-a-phd-opportunity/studentship-projects/3d-modelling-of-the-bone-marrow-tumour-microenvironment-in-pre-leukaemic-disorders