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Preventing malignant transformation in multiple myeloma using gut-derived short chain fatty acids


   Norwich Medical School

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  Prof N Horwood, Dr B Evans  No more applications being accepted  Competition Funded PhD Project (UK Students Only)

About the Project

Multiple Myeloma (MM) is a haematological cancer caused by abnormal plasma cell expansion in the bone marrow.  MM is preceded by an earlier clinically stable stage termed monoclonal gammopathy of undetermined significance (MGUS). Approximately 1% of people with MGUS will develop MM each year yet there is no clinical intervention to prevent this transformation. Mouse modelling of MGUS suggests that clinical dormancy may be regulated in part by growth controls extrinsic to the tumour cells. Thus, interactions with cells and factors in the bone marrow are key regulators of malignant transformation. 

Gut microbes communicate with the host through microbiota-derived metabolites such as the short-chain fatty acids (SCFAs); various SCFA have been identified as important anti-cancer agents in different cancers. Alterations in the gut microbiome have been documented in MM patients with a reduced number of SCFA-producing bacteria. However, a possible link between SCFA and malignant transformation from MGUS to MM and whether SCFA supplementation can prevent this remains to be explored. 

This project will investigate how gut-derived metabolites influence MM progression using a combination of in vivo mouse models of MGUS and MM, as well as ex vivo analysis of patient samples. Analysis of cellular responses to SCFA will be assessed at the cellular level (FACS, mass cytometry) and at the molecular level (qPCR, RNASeq). This work will generate pre-clinical data for future clinical translation for those living with MGUS. 

The project would be suitable for candidates interested in prevention and therapy of haematological malignancies, gut dysbiosis and bioinformatics. At Norwich Medical School, the student will receive training in in vivo disease models, in vitro dissection of disease mechanisms, and computational modelling as well as training in scientific writing, presentation, data management, statistical analysis and will be encouraged to attend and present at national and international conferences. 


Funding Notes

This PhD project is a Faculty of Medicine and Health Sciences competition for funded studentships. The studentships are funded for 3 years and comprise UK tuition fees, an annual stipend of £15,609 (2021/22 rate) and £1,000 per annum to support research training. International applicants (including EU) may apply but are required to fund the difference between UK and International tuition fees (details of tuition fees can be found on our website https://www.uea.ac.uk/study/fees-and-funding/fees).

References

i) The glycosphingolipid inhibitor eliglustat inhibits autophagy in osteoclasts to increase bone mass and reduce myeloma bone disease. H. Leng, H. Zhang, L. Li, ….. A.K. Simon and N.J. Horwood. bioRxiv 2021.02.05.429906; doi: https://doi.org/10.1101/2021.02.05.429906
ii) Glycosphingolipid synthesis inhibition limits osteoclast activation and myeloma bone disease. Ersek A, Xu K, Antonopoulos A, …. Horwood NJ and Karadimitris A. J Clin Invest. 2015 Jun;125(6):2279-92. doi: 10.1172/JCI59987.
iii) Antibiotic-induced disturbances of the gut microbiota result in accelerated breast tumor growth. McKee AM, Kirkup BM, … Hall LJ, Robinson SD. iScience. 2021 Aug 20;24(9):103012. doi: 10.1016/j.isci.2021.103012
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