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Prof Alex Bullock
No more applications being accepted
Funded PhD Project (UK Students Only)
Oxford
United Kingdom
Biochemistry
Bioinformatics
Biophysics
Cancer Biology
Cell Biology
Molecular Biology
Structural Biology
About the Project
How to apply
To apply to this project, you will need to submit an application to the DPhil in Clinical Medicine, listing this project in the 'Proposed field and title of research project' field of the application form.
Gain of function mutations in cell signalling networks are a major driver of cancer, as well as inherited diseases (1-2). An understanding of the structures and mechanisms of cell signalling proteins are therefore critical for the design of new targeted drug treatments (3-4). The receptor serine kinase ALK2, also known as ACVR1, is a member of the BMP/TGF-beta receptor family that acquires activating intracellular mutations in the childhood brain tumour DIPG (diffuse intrinsic pontine glioma)(ref), as well as the rare musculoskeletal disease FOP (fibrodysplasia ossificans progressiva)(1-3). This project will focus on the structural mechanisms of its interaction with downstream signaling effectors and repressors that contribute to these diseases. In addition, the project will contribute to our ongoing drug discovery efforts (1). Key questions include: how does ALK2 activity drive disease? How do the mutations affect the receptor’s structure and function? How are different signalling pathways affected? What protein-protein interactions are changed? Can highly specific inhibitors be developed for use in children?
Training Opportunities
This multidisciplinary DPhil project will use structural, biophysical, cellular and chemical biology approaches. You will learn aspects of molecular biology from routine cloning and mutagenesis to protein expression and purification using bacterial, and human cells. Wild-type and mutant proteins and their signalling complexes will be analysed using bioinformatic, cellular, biochemical and biophysical techniques (including mass spectrometry, fluorescence, surface plasmon resonance and calorimetry). You will make use of state of art facilities for protein crystallisation, X-ray diffraction and structure determination. The student will also benefit from extensive collaborations with international collaborators, patients and disease foundations, and clinicians interested in drug development.
Please email [Email Address Removed] for questions about the project.
Funding Notes
Oxford-The Simcox Family Graduate Scholarship
One full scholarship is available for applicants who are ordinarily resident in the United Kingdom and who are applying to a DPhil course at Oxford related to Fibrodysplasia Ossificans Progressiva. The scholarship covers course fees and a grant for living costs for full-time students of at least £18,000 per year. Awards are made for the full duration of your fee liability for the 4 year course. The scholarship is jointly funded by the University and the Simcox family.
One full scholarship is available for applicants who are ordinarily resident in the United Kingdom and who are applying to a DPhil course at Oxford related to Fibrodysplasia Ossificans Progressiva. The scholarship covers course fees and a grant for living costs for full-time students of at least £18,000 per year. Awards are made for the full duration of your fee liability for the 4 year course. The scholarship is jointly funded by the University and the Simcox family.
References
1) Taylor, KR et al. (2014) Recurrent activating ACVR1 mutations in diffuse intrinsic pontine glioma. Nat Genet. 46, 457-461.
2) Taylor, KR et al. (2014) ACVR1 mutations in DIPG: lessons learned from FOP. Cancer Res. 74, 4565-70.
3) Chaikuad, A et al. (2016) Structural Basis of Intracellular TGF-β Signaling: Receptors and Smads. Cold Spring Harb Perspect Biol. 8(11),a022111.
4) Chaikuad, A et al. (2012) Structure of the bone morphogenetic protein receptor ALK2 and implications for fibrodysplasia ossificans progressiva. J Biol Chem. 287, 36990-8.
5) Williams, E et al. (2021) Saracatinib is an efficacious clinical candidate for fibrodysplasia ossificans progressiva. JCI Insight 6, e95042.
6) Fortin, J et al. (2020) Mutant ACVR1 Arrests Glial Cell Differentiation to Drive Tumorigenesis in Pediatric Gliomas. Cancer Cell. 37, 308-323.
2) Taylor, KR et al. (2014) ACVR1 mutations in DIPG: lessons learned from FOP. Cancer Res. 74, 4565-70.
3) Chaikuad, A et al. (2016) Structural Basis of Intracellular TGF-β Signaling: Receptors and Smads. Cold Spring Harb Perspect Biol. 8(11),a022111.
4) Chaikuad, A et al. (2012) Structure of the bone morphogenetic protein receptor ALK2 and implications for fibrodysplasia ossificans progressiva. J Biol Chem. 287, 36990-8.
5) Williams, E et al. (2021) Saracatinib is an efficacious clinical candidate for fibrodysplasia ossificans progressiva. JCI Insight 6, e95042.
6) Fortin, J et al. (2020) Mutant ACVR1 Arrests Glial Cell Differentiation to Drive Tumorigenesis in Pediatric Gliomas. Cancer Cell. 37, 308-323.
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