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
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?
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.
For informal queries, contact: alex.bull...@sgc.ox.ac.uk
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,
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.