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Haematopoietic stem cell dysfunction in ageing and disease


   Institute of Cancer and Genomic Sciences

  Prof J Frampton,  Applications accepted all year round  Self-Funded PhD Students Only

About the Project

Adult organs are maintained by specialised stem cells that persist throughout life thanks to their ability to make exact copies of themselves, all the time retaining the ability to on demand produce the differentiated component cells of the tissue of which they are a part. The tight control of stem cell behaviour is critical in enabling them to function effectively and involves a complex interplay between internal (‘intrinsic’) mechanisms, largely involving the control of gene transcription, and external (‘extrinsic’) influences from the stem cell environment (‘niche’). Changes in both intrinsic or extrinsic mechanisms can underlie the emergence of diseases such as cancer or the decline in stem cell function with age. 

Our laboratory is particularly interested in adult haematopoietic (blood) stem cells that rely on the critical transcription factor MYB. The student will use a combination of genetic approaches to study how MYB or the genes that it regulates influence stem cell function. Analysis of stem cell function will include both in vivo and in vitro assays as well as a range of cellular and molecular approaches, often performed at the single-cell level, including transcriptional profiling and flow cytometry-based assessments of phenotype and signalling. Studies will involve both animal models and human samples. Particular aspects of current studies that the student could be engaged on, include (i) trying to understand how inherited variation in MYB expression affects the prevalence of age-related disease in the blood, and (ii) determining how translational or post-translational control of MYB protein levels fine-tunes its ability to maintain a fully competent stem cell state. 


Funding Notes

In addition to the appropriate university tuition fee (UK or International postgraduate research rate) the student will be expected to provide a bench fee, which will be project-dependent but likely to be in the range of £10-15K per year for time spent in the laboratory. Research projects will typically require a minimum of 3 years in the laboratory, although this could extend to 3 ½ years. Thesis write-up can be additional to this time up to a maximum of 4 years from the registered start date – any time in write-up only mode will only incur a minimal tuition fee.

References

1. Stem Cells: Biology and Application. Clarke, M.L. and Frampton, J. Taylor & Francis Inc. 2020 ISBN: 9780815345114
2. Determining c-Myb protein levels can isolate functional hematopoietic stem cell subtypes. Sakamoto H, Takeda N, Arai F, Hosokawa K, Garcia P, Suda T, Frampton J, Ogawa M. Stem Cells. 2015 Feb;33(2):479-90. doi: 10.1002/stem.1855. PMID: 25329760
3. Transcriptional regulation of SPROUTY2 by MYB influences myeloid cell proliferation and stem cell properties by enhancing responsiveness to IL-3. Clarke M, Volpe G, Sheriff L, Walton D, Ward C, Wei W, Dumon S, García P, Frampton J. Leukemia. 2017 Apr;31(4):957-966. doi: 10.1038/leu.2016.289. Epub 2016 Oct 17. PMID: 27748374
4.Genetically-determined Myb insufficiency directly impacts on proteostasis in hematopoietic stem cells predisposing to age-related myeloid neoplasia. M.L. Clarke, R.B. Lemma, D.S. Walton, G. Volpe, B. Noyvert, O.S. Gabrielsen, J. Frampton. doi: https://doi.org/10.1101/2021.09.04.458970

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