About the Project
Using induced pluiripotent stem cells (iPSC) and CRISPR/Cas9 gene editing to understand how mesenchymal stem cells of the bone marrow sustain leukaemia development. We will use the knowledge generated from our previous work to disrupt the cellular and molecular mechanism which allow for protection of acute myeloid leukaemia cells (AML) in the bone marrow niche. To this end we will combine studies of genetically modified MSC with mouse studies and analysis of human samples, with the aim of identifying molecular and pharmacological strategies to treat disease and counteract the adverse effects of MSC on leukaemia cell growth.
AML is a highly lethal disease in which the overall survival rate has not improved over the last 25 years. AML is primarily a disease of the elderly with three quarters of patients diagnosed after the age of 60 and presently the majority of patients with acute myeloid leukaemia (AML) die within a year of diagnosis. Increasing doses, or variations of cytotoxic chemotherapy regimens, have been trialed in recent decades but without success and accordingly it is envisaged that novel approaches to treating AML, informed by an improved scientific understanding of the disease, will be needed to improve outcomes for patients in the future.
Training will be provided in the areas of AML biology, biology of MSC, iPSC differentiation, advanced flow cytometry, single cell sorting, mouse genetics and CRISPR/Cas9-based genome editing. As well as the specific training detailed above, students will have access to high-quality training in scientific and generic skills, as well as access to a wide-range of seminars and training opportunities.
For more information on the supervisor for this project, please go here: https://people.uea.ac.uk/en/persons/s-rushworth
The type of programme: PhD
The start date of the project: 01/10/2019
Mode of study: Full time
Entry requirements: Acceptable first degree in Biological Sciences or equivalent and minimum entry requirements is 2:1.
The standard minimum entry requirement for the studentship competition is 2:1 (or equivalent)
References
i) Leukemic blasts program bone marrow adipocytes to generate a protumoral microenvironment. Shafat MS, Oellerich T, Mohr S, Robinson SD, Edwards DR, Marlein CR, Piddock RE, Fenech M, Zaitseva L, Abdul-Aziz A, Turner J, Watkins JA, Lawes M, Bowles KM, Rushworth SA. Blood. 2017 Mar 9;129(10):1320-1332
ii) PGC-1α driven mitochondrial biogenesis in stromal cells underpins mitochondrial trafficking to leukemic blasts. Marlein CR, Zaitseva L, Piddock RE, Raso-Barnett L, Scott MA, Ingham CJ, Collins A, Bowles KM, Rushworth SA. Leukemia. 2018 Sep;32(9):2073-2077.
iii) Acute myeloid leukemia induces protumoral p16INK4a-driven senescence in the bone marrow microenvironment. Abdul-Aziz AM, Sun Y, Hellmich C, Marlein CR, Mistry J, Forde E, Piddock RE, Shafat MS, Morfakis A, Mehta T, Di Palma F, Macaulay I, Ingham CJ, Haestier A, Collins A, Campisi J, Bowles KM, Rushworth SA. Blood. 2019 Jan 31;133(5):446-456.
iv) Isogenic Pairs of hiPSC-CMs with Hypertrophic Cardiomyopathy/LVNC-Associated ACTC1 E99K Mutation Unveil Differential Functional Deficits. Smith, J. G., Owen, T., Bhagwan, J. R., Mosqueira, D., Scott, E., Mannhardt, I., Patel, A., Barriales-Villa, R., Monserrat, L., Hansen, A., Eschenhagen, T., Harding, S. E., Marston, S. & Denning, C. 13 Nov 2018 In : Stem Cell Reports. 11, 5, p. 1226-1243
v) CRISPR/Cas9 editing in human pluripotent stem cell-cardiomyocytes highlights arrhythmias, hypocontractility, and energy depletion as potential therapeutic targets for hypertrophic cardiomyopathy. Mosqueira, D., Mannhardt, I., Bhagwan, J. R., Lis-Slimak, K., Katili, P., Scott, E., Hassan, M., Prondzynski, M., Harmer, S. C., Tinker, A., Smith, J. G. W., Carrier, L., Williams, P. M., Gaffney, D., Eschenhagen, T., Hansen, A. & Denning, C. 14 Nov 2018 In : European Heart Journal. 39, 43, p. 3879-3892
