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Characterising the organisation and dynamics of the IMS and cytoskeleton in human iPSC-derived megakaryocytes and platelet production


   Institute of Cardiovascular Sciences

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  Dr S Thomas, Prof Neil Morgan  No more applications being accepted  Funded PhD Project (UK Students Only)

About the Project

Research interests/description of main research theme:

Blood clotting requires recruitment of platelets (specialised blood cells) to the site of injury to prevent bleeding. Platelet production is a tightly regulated process where an average adult produces approximately 1.5 x 10^11 platelets per day from its progenitor cell, the megakaryocyte. Disruption of platelet production can lead to platelet disorders, including thrombocytopenia, thrombocytosis and platelet dysfunction, all of which have serious implications for cardiovascular health. The clinical requirement for platelet transfusions continues to rise (by ~25% between 2007-14 in the UK) due to an aging population, and increased by the number of patients with haematological malignancies and advances in treatments, such as chemotherapy. To meet the current and projected demand for blood platelets for transfusion, we need to move to robust in vitro platelet production systems. These will include utilising human induced pluripotent stem cell-derived megakaryocytes (hiPSC-MKs) as a source of progenitor cells. 

The Invaginated Membrane System (IMS) is a critical reservoir of lipid plasma membrane that forms in maturing megakaryocytes and is critical for platelet production. However, the details of its formation are not fully understood and has never been studied in hiPSC-MKs. In this project we will investigate mechanisms that drive proper IMS and platelet formation and how the microenvironment influences this process. This will include studying a patient mutation in the platelet/megakaryocyte specific protein Glycoprotein1b that causes reduced platelet production. This knowledge will help in improving the platelet producing potential of iPSC-MKs in vitro, and also in our understanding of diseases relating to platelet count and dysfunction.

The successful student will join the Birmingham Platelet Group based in the Medical School at the University of Birmingham, a large multi-disciplinary research group in the Institute of Cardiovascular Sciences. The group has expertise in platelets, megakaryocytes, genomics and microscopy and so the student will receive excellent training in a wide range of techniques including stem cell culture and differentiation, advanced fluorescence microscopy, platelet and megakaryocyte cell biology and image analysis.

Person Specification

Applicants should have a strong background in Cellular and Molecular Biology, and ideally a background and interest in stem cells, the cytoskeleton and/or advanced fluorescence microscopy. They should have a commitment to research in discovery and translational science and hold or expect to obtain at least an Upper Second Class Honours Degree in Biomedicine, Biology, or other relevant subject. 

How to apply

Informal enquiries should be directed to Dr Steve Thomas ([Email Address Removed]) or Professor Neil Morgan ([Email Address Removed]) 

Applications should be directed to Dr Steve Thomas (email [Email Address Removed]). To apply, please send: 

• A detailed CV, including your nationality and country of birth;

• Names and addresses of two referees; 

• A covering letter highlighting your research experience/capabilities;

• Copies of your degree certificates with transcripts;

• Evidence of your proficiency in the English language, if applicable.


Funding Notes

3 Year British Heart Foundation funded PhD studentship

References

1. Khan AO, Slater A, Maclachlan A, Nicolson PLR, Pike JA, Reyat JS, Yule J, Stapley R, Rayes J, Thomas SG, Morgan NV (2022) Post-translational polymodification of β1-tubulin regulates motor protein localisation in platelet production & function. Haematologica 107: 243-259
2. Thomas SG & Poulter NS (2020) Seeing is believing: Use of advanced imaging to study platelets and megakaryocytes. Platelets 31(5): 549-550
3. Zuidscherwoude M, Haining EJ, Simms VA, Watson S, Grygielska B, Hardy AT, Bacon A, Watson SP Thomas SG (2021) Loss of mDia1 and Fhod1 impacst platelet formation but not function. Platelets 32(8): 1051-1062
4. Khan AO, Maclachlan A, Lowe GC, Nicolson PLR, Al-Ghaithi R, Thomas SG, Watson SP, Pike JA Morgan NV (2020) High-throughput spreading analysis: a toll for the diagnosis of platelet-blased bleeding disorders. Haematologica 105(3): e124-e128
5. Poulter NS & Thomas SG (2015) Cytoskeletal regulation of platelet formation: Coordination of F-actin and microtubules. Int J Biochem & Cell Biol 66:67-74
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