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 6 BHF Centre 3-Year Interdisciplinary PhD projects to commence in October 2014:
(Please note that further information on these projects will become available soon.)
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)
Molecular imaging of inflammation and extracellular matrix remodelling after MI (Prof Rene Botnar, Prof Ajay Shah)
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.
Clinical, biochemical and cellular phenotyping of HCM-associated mutations in the titin gene TTN (Prof Mathias Gautel, Dr Gerry Carr-White)
Prof Rene Botnar, Prof Ajay Shah
Inflammation plays an important role in many diseases including atherosclerosis, myocardial infarction, heart failure and transplantation. Recent studies reinforce the central role of blood monocytes in the acceleration of atherosclerosis as demonstrated in mouse models of myocardial infarction (MI) in which increased numbers of circulating monocytes become available as a result of the MI and subsequently home to sites of endothelial dysfunction thereby accelerating plaque formation. MRI of 19F labelled nanoparticles in atherosclerosis and infarct healing allows selective imaging of inflammatory cells in vivo without any contamination from background signal and may also allow for more accurate signal quantification. During wound healing and subsequent formation of the fibrotic scar, the synthesis of extracellular matrix (ECM) proteins is upregulated. Elastin has been identified as a key ECM protein decisive for infarct stabilization and preservation of ventricularfunction. The abundance of elastin within the myocardial scar makes this ECM protein a promising imaging biomarker for molecular MRI.The objectives of this PhD project are to (1) evaluate the merits of 19F labelled nanoparticles for the selective imaging of inflammatory cells (e.g. macrophages, monocytes) after myocardial infarction and (2) to investigate the merits of an elastin and collagen binding contrast agent for imaging of extracellular matrix remodelling and its relationship with functional recovery.
You will learn about the use of molecular cardiac MRI, histology/immunohistochemistry, nanoparticles, contrast agents, flow cytometry, western blotting and you will be working in an interdisciplinary team of biologists, chemists, and imaging and clinician scientists.
Requirements: MSc in biology or medicine
Makowski MR, Wiethoff AJ, Blume U, Cuello F, Warley A, Jansen CH, Nagel E, Razavi R, Onthank DC, Cesati RR, Marber MS, Schaeffter T, Smith A, Robinson SP, Botnar RM. Assessment of atherosclerotic plaque burden with an elastin-specific magnetic resonance contrast agent. Nat Med. 2011 Mar;17(3):383-8.
Protti A, Dong X, Andia ME, Yu B, Dokukina K, Chaubey S, Phinikaridou A, Vizcay-Barrena G, Taupitz M, Botnar RM, Shah AM. Assessment of inflammation with a very small iron-oxide particle in a murine model of reperfused myocardial infarction. J Magn Reson Imaging. 2013 Sep 4.
Flögel U, Ding Z, Hardung H, Jander S, Reichmann G, Jacoby C, Schubert R, Schrader J. In vivo monitoring of inflammation after cardiac and cerebral ischemia by fluorine magnetic resonance imaging. Circulation. 2008 Jul 8;118(2):140-8.
Please ensure to include Ref # 03/14PHD/Botnar on your application.
Non-invasive Assessment of Left Ventricular Pressure, Myocardial Wall Stress and Work (Prof Phil Chowienczyk, Dr Jordi Alastruey)
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.
MicroRNAs in Heart Failure (Prof Manuel Mayr, Prof Ajay Shah)
Ref # 03/14PHD/Chowienczyk
Prof Phil Chowienczyk, Dr Jordi Alastruey
This project will investigate the accuracy of novel non-invasive methodology for measurement of left ventricular (LV) pressure, myocardial wall stress and work. These measurements will be obtained from aortic blood flow and ventricular wall motion acquired using magnetic resonance imaging (MRI)/ echocardiography and brachial blood pressure obtained form an MRI-compatible oscillometric cuff-based device. LV pressure and wall stress are fundamental biophysical drivers of the myocardial hypertrophy that underlies hypertensive heart disease and heart failure. Myocardial work is closely linked to oxygen demand and, therefore, in the presence of coronary artery disease, determines myocardial ischaemia. The project will combine clinical data with computational modelling to advance the characterisation of LV mechanics with potentially huge scientific, clinical and commercial impact. The student will learn several interdisciplinary skills: cardiovascular physiology, theoretical models of the human circulatory system, computer implementation of these models using data available in the clinic, and image segmentation and geometrical reconstruction.
Guilcher A, Brett S, Munir S, Clapp B, Chowienczyk PJ. Estimating central SBP from the peripheral pulse: influence of waveform analysis and calibration error. J Hypertens 2011; 29:1357–1366.
Alastruey J, Khir AW, Matthys KS, Segers P, Sherwin SJ, Verdonck PR, Parker KH, Peiro J. Pulse wave propagation in a model human arterial network: Assessment of 1-D visco-elastic simulations against in vitro measurements. J Biomech 2011; 44:2250–2258.
Caro et al. The Mechanics of the Circulation. 2012, 2nd ed. http://www.cambridge.org/us/academic/subjects/mathematics/mathematical-modelling-and-methods/mechanics-circulation-2nd-edition
Please ensure to include Ref # 03/14PHD/Chowienczyk on your application.
Characterising the "formin-ome" in heart failure 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.
Ref # 03/14PHD/Ehler
Dr Elisabeth Ehler, Prof Cathy Shanahan
This project aims to establish the signaling mechanisms involved in cross-talk between the nuclear lamina and the actin cytoskeleton in cardiomyocytes by charting the expression levels of the "formin-ome" in healthy and failing human heart using RT-PCR with established primer sets. This will be compared with results from primary neonatal rat cardiomyocytes seeded on substrates with different mechanical stiffness and correlated with the expression levels of lamin A in the different conditions. Selected formin proteins that appear to be most dramatically affected will then be studied more closely for their subcellular localisation in cardiomyocytes and subsequently 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 nucleocytoskeleton of cardiomyocytes and into experimental techniques such as biochemistry, molecular biology, mechanobiology, immunofluorescence & confocal microscopy, and cell culture.
Requirements: BSc in biology, biochemistry or biophysics
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.
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.
Studentships cover Home/EU tuition fees plus offer a stipend at BHF rates (currently £22,278 per annum) for all three years.
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 projects of interest under the ‘Research Proposal’ section. Please note you can only submit one application for all the available PhD projects. If you would like to submit different personal statements according to the different projects, please email firstname.lastname@example.org
- References are not due by the closing date; however, they are expected to be received by the interview date, if invited.
Closing Date: Friday, 10th January, 2014
Interviews: February / March 2014
Should you have any queries please contact Elizabeth Halton, Assistant Divisional Manager, on Elizabeth.email@example.com or (020) 7848 0263.