BHF Centre 3-Year Interdisciplinary PhD Studentships
Applications for the 2014/15 intake are now open.
The King’s College London British Heart Foundation (BHF) Centre of Research Excellence offers an outstanding environment for cardiovascular research training. It includes a large number of internationally rated investigators whose expertise encompasses a very broad range of cardiac and vascular biomedicine. The unit performed exceedingly well in the recent RAE, being the only institution to be in the top 3 both on average quality score and research power.
We have 4 BHF Centre 3-Year Interdisciplinary PhD projects to commence in October 2014:
New light on the regulation of cardiac contractility: time-resolved FRET measurements of protein domain motions during calcium activation (Prof Malcolm Irving, Dr Simon Ameer-Beg)
Clinical, biochemical and cellular phenotyping of HCM-associated mutations in the titin gene TTN (Prof Mathias Gautel, Dr Gerry Carr-White)
Ref # 03/14PHD/Irving
Prof Malcolm Irving, Dr Simon Ameer-Beg
This project will develop new physics-based methods to follow changes in the structure of the regulatory proteins in heart muscle cells on the timescale of the heartbeat, with the aim of better understanding the normal control of heart muscle contraction and its impairment in heart disease. It will use Förster Resonance Energy Transfer (FRET) to measure nanometer-scale changes in protein structure on the millisecond timescale in cardiac muscle cells. The project will combine aspects of photonics, instrumentation (hardware and software), and physiological and polarised fluorescence measurements on isolated heart muscle cells into which fluorescently labelled proteins have been introduced. The applicant should have an undergraduate degree in experimental physics or equivalent and an ambition to apply physics to biology. Training in all the relevant biological methods will be provided.
Knowles, A. C., Irving, M. & Sun, Y.-B. (2012). Conformation of the troponin core complex in the thin filaments of skeletal muscle during relaxation and active contraction J. mol. Biol. 421, 125-137.
Matthews, D.R., Carlin, L.M., Ofo, E., Barber, P.R., Vojnovic, B., Irving, M., Ng, T., & Ameer-Beg, S,M. (2010). Time-lapse FRET microscopy using fluorescence anisotropy. J. Micros. 237, 51-62.
Please ensure to include Ref # 03/14PHD/Irving on your application.
Closing Date: 31 March, 2014 (Midnight BST)
MicroRNAs in Heart Failure (Prof Manuel Mayr, Prof Ajay Shah)
Prof Mathias Gautel, Dr Gerry Carr-White
Next-generation sequencing (NGS) projects are identifying variants in the TTN gene encoding the giant sarcomere protein titin as a major, if not dominant cause of dilated and hypertrophic cardiomyopathies, plus skeletal and combined myopathies with early (paediatric) and late onset. In this project, we will combine comprehensive clinical phenotyping including advanced cardiac imaging with NGS analysis of the titin gene for identification of HCM-associated TTN variants in the GSTT cohort of HCM patients. The project is embedded also in collaborations with Prof. P. Elliott (UCL). The functional impact of TTN variations will be assessed in an integrated programme combining protein characterization for the direct impact of the mutations, with cellular analysis using iPSC-derived cardiomyocyte cultures that allow cellular contractile phenotyping, analysis of stress responses and protein turnover. Techniques will include analysis of full exome sequencing data, classifying TTN variants based on biocomputational criteria (sequence-based homology modelling), biochemical/biophysical characterisation of selected mutations using protein interaction analysis, protein stability (CD spectroscopy and single-molecule force spectroscopy) and use of structural biology (X-ray crystallography) data, and live-cell imaging techniques.
Requirements: MSc medicine/ BSc in biology, biochemistry or biophysics
Elliott, P., C. O'Mahony, P. Syrris, A. Evans, C. Rivera Sorensen, M.N. Sheppard, G. Carr-White, A. Pantazis, and W.J. McKenna, Prevalence of desmosomal protein gene mutations in patients with dilated cardiomyopathy. Circ Cardiovasc Genet, 2010. 3(4): p. 314-22.
Puntmann, V.O., T. Voigt, Z. Chen, M. Mayr, R. Karim, K. Rhode, A. Pastor, G. Carr-White, R. Razavi, T. Schaeffter, and E. Nagel, Native T1 mapping in differentiation of normal myocardium from diffuse disease in hypertrophic and dilated cardiomyopathy. JACC Cardiovasc Imaging, 2013. 6(4): p. 475-84.
Chauveau, C., C. Bonnemann, C. Julien, A.L. Kho, H. Marks, B. Talim, P. Maury, M.C. Arne-Bes, E. Uro-Coste, A. Alexandrovich, A. Vihola, S. Schafer, B. Kaufmann, L. Medne, N. Hübner, R.A. Foley, M. Santi, B. Udd, H. Topaloglu, S.A. Moore, M. Gotthardt, M.E. Samuels, M. Gautel, and A. Ferreiro, Recessive TTN truncating mutations define novel forms of core myopathy with heart disease. Hum Mol Genet, 2013. doi: 10.1093/hmg/ddt494.
Please ensure to include Ref #03/14PHD/Gautel on your application.
Closing Date: 17 March, 2014 (Midnight BST)
Actin and disease: Characterising the "formin-ome" in cardiovascular disease and correlating it with mechanosignalling to the nucleus (Dr Elisabeth Ehler, Prof Cathy Shanahan)
Ref # 03/14PHD/Mayr
Prof Manuel Mayr, Prof Ajay Shah
We are seeking exceptional and highly motivated candidates for an interdisciplinary PhD studentship aiming to address some of the fundamental questions for the regulatory role of microRNAs in cardiac fibrosis. Prof Shah is renowned for investigating heart failure (Shah AM & Mann DL, Lancet 2011). Prof Mayr’s group is at the forefront of microRNA biomarkers for cardiovascular disease and supported by a Leducq Transatlantic Network of Excellence on microRNAs (http://www.vascularmicrornas.com). His proteomics group is equipped with high-resolution mass spectrometry equipment (www.vascular-proteomics.com) and has recently demonstrated that proteomics methods can be more effective for identifying microRNA targets than the use of bioinformatics prediction algorithms (Abonnenc et al, Circ Res 2013).
The combination of proteomics and microRNAs will enable the student to acquire a unique expertise: 1) Training in mass spectrometry and its application to cardiac tissue samples; 2) Molecular biology skills for conducting microRNA research; 3) Working with a systems biology approach by combining animal models of heart failure with proteomics and bioinformatics.
Shah AM, Mann DL. In search of new therapeutic targets and strategies for heart failure: recent advances in basic science. Lancet. 2011 Aug 20;378:704-12.
Abonnenc M, Nabeebaccus AA, Mayr U, Barallobre-Barreiro J, Dong X, Cuello F, Sur S, Drozdov I, Langley S, Lu R, Stathopoulou K, Didangelos A, Yin X, Zimmermann WH, Shah AM, Zampetaki A, Mayr M. Extracellular matrix secretion by cardiac fibroblasts: Role of microRNA-29b and microRNA-30c. Circ Res. 2013 Oct 25;113(10):1138-47.
Please ensure to include Ref # 03/14PHD/Mayr on your application.
Closing Date: 17 March, 2014 (Midnight BST)
Ref # 03/14PHD/Ehler
Dr Elisabeth Ehler, Prof Cathy Shanahan
The mechanical environment of a cell impacts on its cytoskeleton and nucleoskeleton, leading to transcriptional activation and changes in cell morphology. In the failing heart cardiomyocytes respond to the different mechanical environment caused by an increase in extracellular matrix. We want to shed light on the mechanisms of response by investigating the signaling mechanisms involved in cross-talk between the actin cytoskeleton and the nuclear lamina in cardiomyocytes by charting the expression levels of the "formin-ome" in healthy and failing human heart. Formins are well known regulators of the actin cytoskeleton and their role in different diseases is only beginning to be understood. Initially we will establish the formin family members that are most responsive to altered mechanical environments in the heart. Selected formins will then be analysed by gain of function (overexpression of epitope tagged constitutively active constructs) and loss of function (RNAi knockdown) experiments in primary cultures of neonatal rat cardiomyocytes. Formin expression will also be analysed in animal models of heart failure induced by nuclear lamina disruption and in the muscle Lim protein (MLP) knockout mouse, the first genetically modified animal model for dilated cardiomyopathy. The project will give the student an excellent insight into the cyto- and nucleoskeleton of cardiomyocytes and into cutting edge experimental techniques such as molecular biology, mechanobiology, immunofluorescence, confocal microscopy and cell biology.
Iskratsch, T., S. Lange, J. Dwyer, A.L. Kho, C. dos Remedios and E. Ehler (2010): Formin follows function: a muscle-specific isoform of FHOD3 is regulated by CK2 phosphorylation amd promotes myofibril maintenance. J. Cell Biol. 191, 1159-1172.
Ragnauth CD, Warren DT, Liu Y, Tajsic T, Shroff R, McNair R, Figg N, Skepper J, Shanahan CM. (2010). Prelamin A acts to accelerate vascular smooth muscle cell senescence and is a novel biomarker of human vascular ageing. Circulation 121:2200-2210.
Please feel free to email Dr Ehler directly regarding any queries.
Please ensure to include Ref # 03/14PHD/Ehler on your application.
Closing Date: 10 March, 2014 (Midnight BST)
Entry requirements and eligibility
Applicants should have (or expect to obtain) a good 2:1 or 1st class undergraduate degree in a relevant subject. Alternatively, if applicants have (or expect to obtain) an MSc degree, a merit or distinction is required.
Applicants must also meet BHF residency requirements.
The Studentship will cover full fees at the Home/EU rate and provide a tax-free stipend at the BHF rates. The current 2013/14 BHF rates are: £22,278 (1st year); £24,093 (2nd year); £26,057 (3rd year). The 2014/15 rates will at least match this. £1000 is also given for travel to conferences abroad.
How to Apply
Please apply online at https://myapplication.kcl.ac.uk/ following these steps:
- Register a new account / login.
- Open a new application.
- Select the programme:
1. Choose ‘Research degrees’; 2. Enter ‘Cardio’, then Search; 3. Choose: Cardiovascular Research Division MPhil/PhD (Full-time); 4. Choose: ‘October 2014’ as the start date (your application cannot be considered if submitted under the incorrect programme)
- Complete your application, ensuring you name or reference your project of interest under the ‘Research Proposal’ section.
- References are not due by the closing date; however, they are expected to be received by the interview date, if invited.
Closing Date: Vary by project, see above
Interviews: March / April 2014
Should you have any queries please contact Elizabeth Halton, Assistant Divisional Manager, on Elizabeth.email@example.com or (020) 7848 0263.