About the Project
Protein kinase G (PKG) and protein kinase A (PKA) are crucially important kinases in the cardiovascular system.
PKG is the end effector kinase that responds to elevations in cGMP which result from elevations in nitric oxide (NO). PKA is the end effector kinase that responds to elevations in cAMP resulting from beta-adrenergic signalling. In addition to being and being activated by cyclic nucleotides, PKGI and PKAI each also form disulfide bonds during pro-oxidant stimuli.
This project is aimed at understanding the complex relationships between cyclic nucleotide binding to and the redox state of these kinases. Such studies are important given their important roles in the cardiovascular system and the regulation or dysregulation that oxidative stress can provide. These studies may provide new insight to the role of oxidative stress in the maintenance of cardiovascular health and how this may go wrong during disease.
These studies will be challenging and utilise multiple, complementary techniques and approaches, including: Site directed mutagenesis, cell transfection, recombinant protein expression and purification, as well as binding assays involving direct fluorescence polarisation, MicroScale Thermophoresis or surface plasmon resonance. Hands-on practical experience in these techniques, as well as those relating to redox protein biochemistry (especially of kinases) would be highly desirable.
For further information, and details of how to apply, please see our website: www.kcl.ac.uk/lsm/research/divisions/cardio/study/phd/BHFCREPhD.aspx
Funding Notes
Eligibility:
Candidates must possess, or be expected to achieve, a 1st or good upper 2nd class degree in a relevant subject.
Studentships cover tuition fees at the Home/EU rate plus offer a stipend at BHF rates (currently starting at £22,278 per annum) for all three years.
Funding:
Exceptional candidates who qualify as International Students will be considered, if in possession of documented support to cover the tuition fee differential [currently ca £15,000 pa]).
References
Further reading includes:
1. Scotcher J, Prysyazhna O, Boguslavsky A, Kistamas K, Hadgraft K, Martin E D, Worthington J, Rudyk
O, Cutillas P. R, Cuello F, Shattock M J. , Marber M. S, Conte M R, Greenstein A, Greensmith D J,
Venetucci L, Timms J F, Eaton P (2016). Disulfide-activated protein kinase G Iα regulates diastolic
relaxation of the heart and fine-tunes the Frank-Starling response. Nature Communications (in press).
2. Burgoyne JR, Rudyk O, Cho H, Prysyazhna O, Evans R, Ng T, Schröder K, Brandes RP, Shah AM,
Eaton P (2015). Deficient angiogenesis in redox-dead Cys17Ser PKARI knock-in mice. Nature
Communications 6, article number:7920
3. De Nicola GF, Martin ED, Chaikuad A, Bassi R, Clark J, Martino L, Verma S, Sicard P, Tata R,
Atkinson RA, Knapp S, Conte MR, Marber MS (2013). Mechanism and consequence of the
autoactivation of p38α mitogen-activated protein kinase promoted by TAB1. Nat Struct Mol Biol.
20(10):1182-90. doi: 10.1038/nsmb.2668.
4. Prysyazhna O, Rudyk O, Eaton P (2012). Single atom substitution in mouse protein kinase G
eliminates oxidant sensing to cause hypertension. Nature Medicine. 18(2):286-90.
5. Burgoyne JR, Madhani M, Cuello F, Charles RL, Brennan JP, Schröder E, Browning DD and Eaton P
(2007). Cysteine redox sensor in PKGI enables oxidant-induced activation without nitric oxide
pathway. Science 317:1393-1397.
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