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Dietary Intervention to Prevent Myeloma Cancer Progression (HORWOODN_U23FMH)


   Norwich Medical School

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  Prof N Horwood  No more applications being accepted  Competition Funded PhD Project (Students Worldwide)

About the Project

Background 

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. Alterations in the bone marrow (BM) microenvironment are thought to play a role in this evolution and that changes in the gut microbiome leads to alterations in inflammatory pathways and BM microenvironment. Thus, dysbiosis may impact tumorigenesis in MM and promote MGUS to MM transformation. 

Dried plums (prunes) have been used for centuries to regulate gut activity, however recent studies have demonstrated that the carbohydrates and polyphenols found in prunes act as prebiotics. This results in favourable changes in the microbiota and an increase in short chain fatty acid (SCFA) production, n-butyrate and propionate – promoting bone health and reducing inflammation.  Anti-cancer properties of SCFA have been identified in different cancers and a reduction in SCFA-producing bacteria is observed in MM patients, however a possible link between dietary intervention and malignant transformation from MGUS to MM remains to be explored. 

Research Methodology 

This project will investigate how dried plums alter gut-derived metabolites to influence MM progression using a combination of in vivo mouse models of MGUS and MM, and in vitro cellular mechanistic studies. Analysis of cellular responses to dietary supplementation with dried plums 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. 

Training 

The project would be suitable for candidates interested in prevention and therapy of haematological malignancies, gut dysbiosis and bioinformatics. The student will receive training in in vivo disease models, in vitro disease mechanisms, and computational modelling. Training in scientific writing, presentation, data management, statistical analysis and presentation at national and international conferences will be encouraged. 


Funding Notes

This PhD project is in a Faculty of Medicine and Health Sciences competition for funded studentships. These studentships are funded for 3 years and comprise UK fees, an annual stipend of £17,668 and £1,000 per annum for research training (RTSG). Overseas applicants (including EU) may apply but are required to fund the difference between Home and International tuition 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. Nature Communications, in press 2022
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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