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Molecular pathogenesis of the myelodysplastic syndromes: investigation of the molecular mechanisms involved in disease initiation and progression in the myeloid malignancy myelodysplastic syndromes (MDS)

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  • Full or part time
    Dr J Boultwood
    Dr A Pellagatti
  • Application Deadline
    No more applications being accepted
  • Self-Funded PhD Students Only
    Self-Funded PhD Students Only

Project Description

The main focus of our group is the investigation of the molecular mechanisms involved in disease initiation and progression in the myeloid malignancy myelodysplastic syndromes (MDS). We use a variety of techniques, including next-generation sequencing (RNA-seq), induced pluripotent stem cell (iPSC) technology and CRISPR/Cas9 gene editing, in order to better understand disease pathogenesis and to identify new therapeutic targets and prognostic markers for MDS.

Our study of the MDS transcriptome has yielded valuable insights into the molecular pathophysiology of MDS, and has identified new prognostic markers and therapeutic targets for this disorder. We have provided deep insights into how recurrent gene mutations drive the changes in the MDS transcriptome. Most recently, using RNA-seq we have identified key aberrantly spliced genes and dysregulated pathways in bone marrow CD34+ cells and myeloid precursors of MDS patients with commonly occurring splicing factor mutations. We have performed functional studies involving shRNA-mediated gene knockdown to determine the impact of some of the identified splicing abnormalities on the cellular function in the main haematopoietic cell lineages affected in MDS.

CRISPR/Cas9 is powerful and versatile tool for genome editing, and we have used this technology to to introduce or correct specific gene mutations in leukaemia cells. We are currently using CRISPR/Cas9 gene editing to investigate the impact of recurrent mutations on the MDS phenotype. In addition, we are using iPSC technology and CRISPR/Cas9 to model the myeloid malignancy chronic myelomonocytic leukaemia and for drug discovery.

We also plan to perform single-cell mutation profiling and RNA sequencing to identify new therapeutic targets/treatments from the transcriptomic analysis of single haematopoietic stem cells (HSCs) from MDS patients with splicing factor gene mutations. The analysis of the generated single-cell data will allow for the identification of druggable targets, and drugs known to target them, within different mutation-defined HSC subpopulations in individual MDS patients.

The use of CRISPR/Cas9 and iPSCs for disease modelling and for drug discovery, and single-cell analysis of MDS HSCs are possible areas in which student projects will be undertaken.
Students will be trained in a variety of techniques routinely used in the lab, including next-generation sequencing (RNA-seq), cell culture and lentiviral transduction, iPSC technology and CRISPR/Cas9 gene editing.

Training will be given in the relevant areas. We use a variety of techniques and technologies. Day to day: qRT-PCT; Western blotting; exosome extractions and analysis; laser capture microdissection; FACS; Seahorse metabolic analyses; immunofluorescence. We outsource RNA sequencing; ATAC seq and ChIP seq, but are actively involved in the interpretation of data by our bioinformatician. It is common in this laboratory to import specific techniques / collaborations to address a given experiment. All our students to date have been awarded their doctorate. Our students’ work is often recognised by prizes and awards and national and international meetings.

As well as the specific training detailed above, students will have access to high-quality training in scientific and generic skills, as well as access to a wide-range of seminars and training opportunities through the many research institutes and centres based in Oxford.

The Department has a successful mentoring scheme, open to graduate students, which provides an additional possible channel for personal and professional development outside the regular supervisory framework. We hold an Athena SWAN Silver Award in recognition of our efforts to build a happy and rewarding environment where all staff and students are supported to achieve their full potential.

Funding Notes

Our main deadline for applications for funded places has now passed. Supervisors may still be able to consider applications from students who have alternative means of funding (for example, charitable funding, clinical fellows or applicants with funding from a foreign government or equivalent). Prospective applicants are strongly advised to contact their prospective supervisor in advance of making an application.

Please note that any applications received after the main funding deadline will not be assessed until all applications that were received by the deadline have been processed. This may affect supervisor availability.

References

Pellagatti A, Armstrong RN, Steeples V, Sharma E, Repapi E, Singh S, Sanchi A, Radujkovic A, Horn P, Dolatshad H, Roy S, Broxholme J, Lockstone H, Taylor S, Giagounidis A, Vyas P, Schuh A, Hamblin A, Papaemmanuil E, Killick S, Malcovati L, Hennrich ML, Gavin AC, Ho AD, Luft T, Hellstrom-Lindberg E, Cazzola M, Smith CWJ, Smith S, Boultwood J. Impact of spliceosome mutations on RNA splicing in myelodysplasia: dysregulated genes/pathways and clinical associations. Blood. 2018; 132(12):1225-40.
Yip BH, Steeples V, Repapi E, Armstrong RN, Llorian M, Roy S, Shaw J, Dolatshad H, Taylor S, Verma A, Bartenstein M, Vyas P, Cross NC, Malcovati L, Cazzola M, Hellstrom-Lindberg E, Ogawa S, Smith CW, Pellagatti A, Boultwood J. The U2AF1S34F mutation induces lineage-specific splicing alterations in myelodysplastic syndromes. J Clin Invest. 2017; 127(6):2206-21.
Dolatshad H, Pellagatti A, Liberante FG, Llorian M, Repapi E, Steeples V, Roy S, Scifo L, Armstrong RN, Shaw J, Yip BH, Killick S, Kusec R, Taylor S, Mills KI, Savage KI, Smith CW, Boultwood J. Cryptic splicing events in the iron transporter ABCB7 and other key target genes in SF3B1-mutant myelodysplastic syndromes. Leukemia. 2016; 30(12):2322-31.

Valletta S, Dolatshad H, Bartenstein M, Yip BH, Bello E, Gordon S, Yu Y, Shaw J, Roy S, Scifo L, Schuh A, Pellagatti A, Fulga TA, Verma A, Boultwood J. ASXL1 mutation correction by CRISPR/Cas9 restores gene function in leukemia cells and increases survival in mouse xenografts. Oncotarget. 2015; 6(42):44061-71.

Gerstung M, Pellagatti A, Malcovati L, Giagounidis A, Porta MG, Jadersten M, Dolatshad H, Verma A, Cross NC, Vyas P, Killick S, Hellstrom-Lindberg E, Cazzola M, Papaemmanuil E, Campbell PJ, Boultwood J. Combining gene mutation with gene expression data improves outcome prediction in myelodysplastic syndromes. Nat Commun. 2015; 6:5901.
Pellagatti A, Benner A, Mills KI, Cazzola M, Giagounidis A, Perry J, Malcovati L, Della Porta MG, Jädersten M, Verma A, McDonald EJ, Killick S, Hellström-Lindberg E, Bullinger L, Wainscoat JS, Boultwood J. Identification of gene expression-based prognostic markers in the hematopoietic stem cells of patients with myelodysplastic syndromes. J Clin Oncol. 2013; 31(28):3557-64.

How good is research at University of Oxford in Clinical Medicine?

FTE Category A staff submitted: 238.51

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