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Megakaryocytes, platelets and Malignant Bone Marrow Fibro


Project Description

My group focuses on the biology of megakaryocyte cells - large, rare cells found in the bone marrow that release blood platelets into the circulation and also produce many growth factors and other proteins that regulate blood cell development and the bone marrow microenvironment. We apply state-of-the-art single cell multi-omic approaches to clarify the cellular pathways by which megakaryocytes arise from haematopoietic stem cells. This is important as in certain malignancies, such as myeloproliferative neoplasms (MPNs), megakaryocytes develop abnormally and drive the key pathological features of the disease, including the harmful scarring that destroys the bone marrow in myelofibrosis, the most severe of the MPNs.

The main themes of our research aim to (1) use single cell techniques to identify and validate novel targets for immunotherapy in MPNs (2) identify the molecular drivers of abnormal megakaryocyte development and function (3) identify novel inhibitors of bone marrow fibrosis (4) develop better in vivo and in vitro systems to model myelofibrosis to identify and validate potential targets for therapy.

I am also interested in the role of platelets in the diagnosis and molecular profiling of cancers, both solid tumours as well as blood cancers, and in the changes to megakaryocyte development and platelet production over human ontogeny.

As a clinician scientist, I spend 80% of my time in the lab and 20% in the clinic. I hugely enjoy the opportunities this offers to engage patients with research and also to focus my research on clinically meaningful goals.

My group works closely with that of Professor Adam Mead and also with the Oxford team of Sten Eirik Jacobsen in the Haematopoietic Stem Cell Biology Lab. Students will receive training in state-of-the-art molecular biology techniques, including single cell RNA-sequencing (Smart-Seq-2 and high-throughput droplet based 10x Genomics), advanced cell culture, tissue banking, multiparameter flow cytometry, genome engineering, mass spectrometry, highly-multiplexed in situ proteomic imaging and mouse models of human disease.

We also work with the Computational Biology group of Supat Thongjuea. There will be opportunities to learn programming and advanced bioinformatics, both in the lab and as part of the 10-week Oxford Biomedical Data Science Training Course at the MRC WIMM.

The group is well balanced between clinician scientists and basic scientists, with research assistants, DPhil students, postdoctoral fellows with complementary skills and expertise, well supported by a lab manager and excellent postdoctoral bioinformatician, as well as the outstanding core facilities offered by the MRC WIMM. We have weekly data meetings, journal clubs, social events and a very enjoyable yearly 2-day lab retreat.

We have strong international links and collaborations, including with laboratories in the UK (Cambridge, London), New York (Cornell) and the National Institutes of Health (Bethesda) and also with industry. There will be opportunities for international travel for training, attending meetings and collaborators meetings.

Students will be enrolled on the MRC Weatherall Institute of Molecular Medicine DPhil Course, which takes place in the autumn of their first year. Running over several days, this course helps students to develop basic research and presentation skills, as well as introducing them to a wide-range of scientific techniques and principles, ensuring that students have the opportunity to build a broad-based understanding of differing research methodologies.

Generic skills training is offered through the Medical Sciences Division’s Skills Training Programme. This programme offers a comprehensive range of courses covering many important areas of researcher development: knowledge and intellectual abilities, personal effectiveness, research governance and organisation, and engagement, influence and impact. Students are actively encouraged to take advantage of the training opportunities available to them.

As well as the specific training detailed above, students will have access to a wide-range of seminars and training opportunities through the many research institutes and centres based in Oxford.

All WIMM graduate students are encouraged to participate in the successful mentoring scheme of the Radcliffe Department of Medicine, which is the host department of the WIMM. This mentoring scheme provides an additional possible channel for personal and professional development outside the regular supervisory framework. The RDM also holds an Athena SWAN Silver Award in recognition of our efforts to build a happy and rewarding environment where all staff and students are supported to achieve their full potential.

Funding Notes

Funding for this project is available to scientists through the RDM Scholars Programme, which offers funding to outstanding candidates from any country. Successful candidates will have all tuition and college fees paid and will receive a stipend of £18,000 per annum.
For October 2020 entry, the application deadline is 10th January 2020 at 12 noon (midday).
Please visit our website for more information on how to apply.

References

Single-cell analyses reveal aberrant pathways for megakaryocyte-biased hematopoiesis in myelofibrosis and identify mutant clone-specific targets. Psaila B, Thongjuea, S, Rodriguez Meira A, Li R, O’Sullivan J, Heuston E, Anderson S, Senis Y, Voegtle T, Weinberg O, Calicchio M, Milojkovic D, Roberts I, Bodine D, Mead AJ.
BioRxiv 2019 https://doi.org/10.1101/642819; Invited Resubmission, Molecular Cell


Single-cell approaches reveal novel cellular pathways for megakaryocyte and erythroid differentiation. Psaila, B & Mead, AJM. Blood 2019 Mar 28; 133(13):1427-1435. PMID: 30728145

Unravelling intratumoral heterogeneity through high-sensitivity single-cell mutational analysis and parallel RNA-sequencing. Rodriguez-Meira A, Buck G, Clark SA, Povinelli, BJ, Alcolea-Devesa V, Louka E, McGowan S, Hamblin A, Sousos N, Barkas, N, Giustacchini, A, Psaila B, Jacobsen SEW, Thongjuea S, Mead AJ. Molecular Cell, 2019 Mar 21; 73(6): 1292-1305.e8. PMID: 30765193

Single-cell profiling of human megakaryocyte-erythroid progenitors identifies distinct megakaryocyte and erythroid differentiation pathways. Psaila B, Barkas N, Iskander D, Roy A, Anderson S, Ashley N, Caputo VS, Lichtenberg J, Loaiza S, Bodine DM, Karadimitris A, Mead AJ, Roberts I.
Genome Biol. 2016 May 3;17:83. doi: 10.1186/s13059-016-0939-7. PMID: 27142433

In vivo effects of eltrombopag on platelet function in immune thrombocytopenia: no evidence of platelet activation. Psaila B, Bussel JB, Linden MD, Babula B, Li Y, Barnard MR, Tate C, Mathur K, Frelinger AL, Michelson AD. Blood. 2012 Apr 26;119(17):4066-72. doi: 10.1182/blood-2011-11-393900. Epub 2012 Jan 31.PMID: 22294727

The metastatic niche: adapting the foreign soil. Psaila B, Lyden D. Nat Rev Cancer. 2009 Apr;9(4):285-93. doi: 10.1038/nrc2621. PMID: 19308068

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