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  Dissecting mechanisms that control adult stem cells in health, disease, and ageing


   Department of Cancer and Genomic Sciences

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

About the Project

Research interests/description of main research theme:

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 stem cells that rely on the critical transcription factor MYB, including haematopoietic (blood) and skin stem cells. 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, signalling, and function. 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 skin, 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.

Person Specification

Applicants should have a strong background in biology or medicine. They should have a commitment to biomedical research and hold or realistically expect to obtain at least an Upper Second Class Honours Degree in a relevant subject.

How to apply

Applications should be directed to Dr Mary Clarke ([Email Address Removed]) or Prof Jon Frampton ([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 transcripts;

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

Applicants will be required to attend an interview. This can be conducted face-to-face or by Zoom/Teams.

Biological Sciences (4)

Funding Notes

This project is for self-funded UK or international students
In addition to the tuition fee (UK or International) the student will be expected to provide a bench fee, which will be project-dependent but likely to be in the range of £12-15K per year for time spent in the laboratory. Research projects typically require a minimum of 3 years in the laboratory, this could extend to 3 ½ years. Thesis write-up can be additional to this time up to a maximum of 4 years – any time in write-up only mode will only incur a minimal tuition fee and no bench 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. Overexpression of MYB in the skin induces alopecia and epidermal hyperplasia. Hu Y, Song Z, Chen J, Caulin C. J Invest Dermatol. 2020 Jun;140(6):1204-1213.e5. doi: 10.1016/j.jid.2019.10.013. Epub 2019 Nov 21. PMID: 31758945
4. Myb permits multilineage airway epithelial cell differentiation. Pan JH, Adair-Kirk TL, Patel AC, Huang T, Yozamp NS, Xu J, Reddy EP, Byers DE, Pierce RA, Holtzman MJ, Brody SL. Stem Cells. 2014 Dec;32(12):3245-56. doi: 10.1002/stem.1814. PMID: 25103188
5. 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
6. Clarke, M.L., Lemma, R.B., Walton, D.S., Volpe, G., Noyvert, B., Gabrielsen, O.S. and Frampton, J. (2023) MYB insufficiency disrupts proteostasis in hematopoietic stem cells leading to age-related neoplasia. Blood, 141, 1858-70. doi: 10.1182/blood.2022019138. PMID: 36603185
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