Therapeutic resolution of Myelodysplastic Syndrome (MDS) by natural products

About the project

About the Project Myelodysplastic syndromes (MDS) are a type of blood cancer where the patients do not have enough healthy blood cells. It is the most common adult myeloid malignancy in the UK and has been estimated that around 8,000 and 40,000 new cases are diagnosed each year in the UK and USA, respectively.[1] MDS are a heterogeneous group of clonal haematopoietic stem cell disorders characterized by peripheral blood cytopenias and progenitor expansion. Approximately 30% of patients will transform to secondary acute myeloid leukemia (AML) which has a poor prognosis.[2] There is no cure for MDS. Current management therapies include allogeneic haematopoietic cell transplantation, DNA methytransferase inhibitors (DNMTI), also termed hypomethylating agents (HMA), azacitidine or decitabine. Most MDS patients are not eligible for cell transplantation whilst azacitidine has been shown to modestly improve survival compared to standard care.[3] Once patients stop responding to HMA therapy, however, outcomes are dismal, with a median survival of less than six months.[4] Using unbiased sequencing approaches, we (in collaboration with Washington University, USA) and others have identified mutations in 4 genes including SF3B1, SRSF2, U2AF1, and ZRSR2, which are involved in pre-mRNA splicing in ~50% of patients with MDS, making this cellular pathway the most commonly mutated in MDS.[5-8] Current therapies were established prior to the fact that MDS has substantial splicing abnormalities and hence there is a need to identify novel therapeutic intervention targeting the over-active spliceosomal genes. We have developed high-throughput splicing assays [9-11] [12], screened thousands of natural products and established drugs and identified novel hits. The major objectives of this project are to (a) investigate how overactive splicing contributes to disease pathogenesis and (b) determine whether natural products may provide therapeutic intervention. The project will introduce the student to the broader areas of molecular genetics, biochemistry, drug discovery, pharmacology and translational medicine. The research activities will be undertaken at the School of Pharmacy and Medical Sciences, University of Bradford. The studies will be performed in the recently renovated laboratories provided with state of the art equipments including high-throughput fluorescence and luminescence plate readers, QPCR machines, gel doc systems and modern tissue culture facilities. The research sits in the context of a highly active research environment at the University of Bradford. How to apply Formal applications can be submitted via the University of Bradford web site ; applicants will need to register an account, select 'Postgraduate Research' as the type of course and then use the keyword 'pharmacy'. Applicants should then specify the project title in the 'Research Proposal' section. About the University of Bradford Bradford is a research-active University supporting the highest-quality research. We excel in applying our research to benefit our stakeholders by working with employers and organisations world-wide across the private, public, voluntary and community sectors and actively encourage and support our postgraduate researchers to engage in research and business development activities. Positive Action Statement At the University of Bradford our vision is a world of inclusion and equality of opportunity, where people want to, and can, make a difference. We place equality and diversity, inclusion, and a commitment to social mobility at the centre of our mission and ethos. In working to make a difference we are committed to addressing systemic inequality and disadvantages experienced by Black, Asian and Minority Ethnic staff and students. Under sections 158-159 of the Equality Act 2010, positive action can be taken where protected group members are under-represented. At Bradford, our data show that people from Black, Asian, and Minority Ethnic groups who are UK nationals are significantly under-represented at the postgraduate researcher level. These are lawful measures designed to address systemic and structural issues which result in the under-representation of Black, Asian, and Minority Ethnic students in PGR studies.

Research areas