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Using CRISPR in iPS cells to modify platelet function


School of Biological Sciences

About the Project

"Platelets are the small cells in the blood whose job it is to prevent bleeding. Under normal conditions, when they encounter a damaged blood vessel they become activated and form a thrombus. In cardiovascular disease platelets can form unwanted thrombi which block blood vessels, or break away (embolise) causing blockages elsewhere. This can cause a heart attack or stroke.

Understanding how platelets become activated is key to developing new drugs to prevent these life threatening conditions. However, as platelets lack a nucleus, research into platelet proteins can only go so far without the use of mouse models. This project will use a different approach, instead using iPS cells to generate human platelets (from their pre-cursor cell, the megakaryocyte) in vitro. CRISPR gene editing technology will be used to modify platelet proteins to study their function, without the need to generate mutant mouse lines.

Based in the Institute for Cardiovascular and Metabolic Research, School of Biological Sciences, which provides a multidisciplinary interactive research environment for over 30 research groups, this project will provide an excellent opportunity for training in a wide range of basic molecular and cell biology methods including flow cytometry, immunoprecipitation, as well as specialist training in microscopy techniques such as confocal."

Funding Notes

"This project has received funding from the European Union’s Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement No 766118.

ITN Mobility Rule: You must not have resided or carried out your main activity in the host country for more than 12 months in the last 3 years. Compulsory national service and/or short stays such as holidays are not taken into account.

Early-Stage Researcher: You shall be in the first four years (full-time equivalent research experience) of your research career and must not yet have been awarded a doctoral degree. "

References

"Moreau T, Evans AL, Vasquez L, Tijssen MR, Yan Y, Trotter MW, Howard D, Colzani M, Arumugam M, Wu WH, Dalby A, Lampela R, Bouet G, Hobbs CM, Pask DC, Payne H, Ponomaryov T, Brill A, Soranzo N, Ouwehand WH, Pedersen RA, Ghevaert C. (2016) Large-scale production of megakaryocytes from human pluripotent stem cells by chemically defined forward programming. Nat Commun. 2016 Apr 7;7:11208. doi: 10.1038/ncomms11208

Pollitt, A. Y., Hughes, C. E. and Watson, S. P. (2013) GPVI and CLEC-2. In: Michelson, A. D. (ed.) Platelets. 3rd edition. Academic Press, Amsterdam, pp. 215-231. ISBN 9780123878373 doi: https://doi.org/10.1016/B978-0-12-387837-3.00011-0

Nicolson, P. L. R., Hughes, C. E., Watson, S., Nock, S. H., Hardy, A. T., Watson, C. N., Montague, S. J., Malcor, J.-D., Thomas, M. R., Pollitt, A. Y., Tomlinson, M. G., Pratt, G. and Watson, S. P. (2018) Inhibition of Btk by Btk-specific concentrations of ibrutinib and acalabrutinib delays but does not block platelet aggregation to GPVI. Haematologica, 103 (9). ISSN 1592-8721 doi: https://doi.org/10.3324/haematol.2018.193391

Hughes, C. E. (2018) How to perform aggregometry and lumi-aggregometry in mouse platelets. Platelets. ISSN 0953-7104 doi: https://doi.org/10.1080/09537104.2018.1478074

Mangin, P. H., Onselaer, M.-B., Receveur, N., Le Lay, N., Hardy, A. T., Wilson, C., Sanchez, X., Loyau, S., Dupuis, A., Babar, A. K., Miller, J. L. C., Philippou, H., Hughes, C. E., Herr, A. B., Ariens, R. A., Mezzano, D., Jandrot-Perrus, M., Gachet, C. and Watson, S. P. (2018) Immobilized fibrinogen activates human platelets through GPVI. Hematologica, 103 (5). pp. 898-907. ISSN 1592-8721 doi: https://doi.org/10.3324/haematol.2017.182972

Bye, A. P., Unsworth, A. J., Desborough, M. J., Hildyard, C. A. T., Appleby, N., Bruce, D., Kriek, N., Nock, S. H., Sage, T., Hughes, C. E. and Gibbins, J. M. (2017) Severe platelet dysfunction in NHL patients receiving ibrutinib is absent in patients receiving acalabrutinib. Blood Advances, 1 (26). pp. 2610-2623. ISSN 2473-9529 doi: https://doi.org/10.1182/bloodadvances.2017011999

Lombard, S. E., Pollitt, A. Y., Hughes, C. E., Di, Y., Mckinnon, T., O'Callaghan, C. A. and Watson, S. P. (2017) Mouse podoplanin supports adhesion and aggregation of platelets under arterial shear: a novel mechanism of haemostasis. Platelets. ISSN 0953-7104 doi: https://doi.org/10.1080/09537104.2017.1356919"

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