A scholarship-funded DPhil (PhD) studentship position is available at the SGC, University of Oxford, for the academic year starting October 2017. The closing date for applications will be 12 noon UK time, 6th January 2017. Interviews will take place on 24th & 25th January 2017. Scholarship is available for UK nationals only, but funding options are available for other nationalities. Application and project details are copied below:
Characterisation of the drug target ACVR1/ALK2 Supervisors: Dr Alex Bullock, Dr Gillian Farnie Project Overview A multidisciplinary DPhil project is available using structural, cellular and chemical biology approaches to advance our ongoing drug discovery efforts targeting the BMP receptor kinase ALK2, encoded by the gene ACVR1. Gain of function mutations in the intracellular kinase domain of ALK2/ACVR1 cause the childhood brain tumour DIPG (diffuse intrinsic pontine glioma) and the rare bone disease FOP (fibrodysplasia ossificans progressiva) (Nat Genet. 2014; 46, 457-61). There are currently no effective treatments for either condition and prognosis is poor. The ALK2 kinase is a member of the BMP/TGF-beta receptor family that activates both the Smad transcription factor and p38 MAPK signaling pathways by phosphorylation. Ligands of the BMP/TGF-β superfamily (BMPs, Nodal, Activins, GDFs, TGF-βs) are secreted growth factors well known for their roles in determining stem cell fate and tissue repair. While some members such as GDF11 have been controversially famed as the "elixir of youth" (Science 2014; 344, 649-52), many are oppositely linked to human disease. You will elucidate the molecular mechanisms that cause ALK2 deregulation and characterize the actions and potency of small molecule ALK2 inhibitors in development in our group (J Med Chem 2014; 57, 7900-15). Key questions include: how does ALK2 activity drive cancer? How do the disease mutations affect the receptor's structure and function? How are different signalling pathways affected? What protein-protein interactions are changed? Why do oncogenic ALK2/ACVR1 mutations occur together with specific Histone H3 K27M mutations? Do epigenetic inhibitors improve the efficacy of ALK2 inhibitors? Training Opportunities You will learn about protein structure, cellular signalling and drug discovery. Training will be given in all aspects of molecular biology from routine cloning and mutagenesis to protein expression and purification using bacterial and human cells. Wild-type and mutant proteins will be analysed using bioinformatic, cellular, biochemical and biophysical techniques (including mass spectrometry, fluorescence plate readers and calorimetry). As part of the Structural Genomics Consortium (SGC) 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, patient groups, clinicians and pharmaceutical companies. A named scholarship is available for this project for candidates with UK nationality and residency. http://www.ndm.ox.ac.uk/for-applicants For informal queries, contact: alex.bull...@sgc.ox.ac.uk References Sinha M, Jang YC, Oh J, Khong D, Wu EY, Manohar R, Miller C, Regalado SG, Loffredo FS, Pancoast JR, Hirshman MF, Lebowitz J, Shadrach JL, Cerletti M, Kim MJ, Serwold T, Goodyear LJ, Rosner B, Lee RT, Wagers AJ. (2014). Restoring systemic GDF11 levels reverses age-related dysfunction in mouse skeletal muscle. Science, 344, pp. 649-52. Chaikuad A, Alfano I, Kerr G, Sanvitale CE, Boergermann JH, Triffitt JT, von Delft F, Knapp S, Knaus P, Bullock AN. (2012). Structure of the bone morphogenetic protein receptor ALK2 and implications for fibrodysplasia ossificans progressiva. J. Biol. Chem., 287, pp. 36990-8. Mohedas AH, Wang Y, Sanvitale CE, Canning P, Choi S, Xing X, Bullock AN, Cuny GD, Yu PB. (2014). Structure-activity relationship of 3,5-diaryl-2-aminopyridine ALK2 inhibitors reveals unaltered binding affinity for fibrodysplasia ossificans progressiva causing mutants. J. Med. Chem., 57, pp. 7900-15. Chaikuad A, Bullock AN. (2016). Structural Basis of Intracellular TGF-β Signaling: Receptors and Smads. Cold Spring Harb Perspect Biol, [Epub] Taylor KR, Vinci M, Bullock AN, Jones C. (2014). ACVR1 mutations in DIPG: lessons learned from FOP. Cancer Res., 74, pp. 4565-70. Taylor KR, Mackay A, Truffaux N, Butterfield YS, Morozova O, Philippe C, Castel D, Grasso CS, Vinci M, Carvalho D, Carcaboso AM, de Torres C, Cruz O, Mora J, Entz-Werle N, Ingram WJ, Monje M, Hargrave D, Bullock AN, Puget S, Yip S, Jones C, Grill J. (2014). Recurrent activating ACVR1 mutations in diffuse intrinsic pontine glioma. Nat. Genet., 46, pp. 457-61.
