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Targeting redox-active cysteine residues in protein kinases as a new therapeutic approach to ageing and age-associated diseases

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  • Full or part time
    Prof E Veal
    Prof P Eyers
  • Application Deadline
    No more applications being accepted
  • Competition Funded PhD Project (European/UK Students Only)
    Competition Funded PhD Project (European/UK Students Only)

Project Description

Project Summary
This iCASE BBSRC DTP studentship provides an exciting opportunity to use a diverse range of cutting-edge techniques, and exploit the advantages of different model systems, to elucidate new cell signalling mechanisms that protect against ageing/age-associated diseases.

Research Project
Reactive oxygen species (ROS) cause cell damage that is a major contributor to many diseases, including cancer, neurodegenerative and cardiovascular diseases, which are increasingly prevalent in our ageing population. However, over the last 10 years, our view of how to limit this damage has been revolutionised. This follows the discovery that low levels of ROS have important, positive, signalling functions, that include initiating protective responses that maintain cell viability/organismal health. Despite, the increasing evidence that localised ROS increases can be beneficial, the mechanisms by which these ROS signals are transduced to protect against ageing/age-associated loss of tissue function remain poorly understood. You will be part of a multidisciplinary team combining a range of genetic, biochemical and computational approaches to provide answers to this fundamental question.

Dr Veal’s lab have successfully used a combination of high throughput genetic screening and proteomic approaches in model yeast and worms to identify several novel ROS-regulated kinases. The goal of your project will be to use standard and cutting-edge molecular biological and biochemical techniques (including genome editing, RNAi, immunoblotting and confocal microscopy) to investigate, in collaboration with Professor Eyers in Liverpool, whether ROS-induced oxidation of cysteines in these kinases mediates the positive effects of ROS in cell (Schizosaccharomyces pombe), and animal (Caenorhabditis elegans) models. By elucidating new signalling mechanisms that mediated effects of ROS, this project will provide an essential step towards the goal of therapeutically enhancing ROS-induced protective responses to counteract the effects of ageing. The industrial placement, supervised by Dr Conlon, will allow you to use network pharmacology to identify the next step towards translating these discoveries.

Research environment
Dr Veal, and Professor Eyers, lead active and well-established research groups in the cell signalling fields. Dr Veal’s group https://www.ncl.ac.uk/camb/staff/profile/elizabethveal.html#research is based in the Biosciences Institute at Newcastle University, which is a vibrant, well-equipped and highly successful research institute (ranked 2nd nationally for research outputs in REF2014) with PhD students contributing to the majority of our papers. Professor Eyers leads a highly successful group in the Institute of Integrative Biology at Liverpool University. https://www.liverpool.ac.uk/integrative-biology/staff/patrick-eyers/research/. Dr Nichola Conlon CEO of the industrial partner, Nuchido (based in Newcastle) and an expert in network pharmacology, will supervise the industrial placement, which will provide a fantastic opportunity to experience first-hand the process involved in starting to translate findings from ageing research. Potential applicants are strongly encouraged to contact the lead supervisor [Email Address Removed] for further details before making an application.

HOW TO APPLY
Applications should be made by emailing [Email Address Removed] with a CV (including contact details of at least two academic (or other relevant) referees), and a covering letter – clearly stating your first choice project, and optionally 2nd and 3rd ranked projects, as well as including whatever additional information you feel is pertinent to your application; you may wish to indicate, for example, why you are particularly interested in the selected project(s) and at the selected University. Applications not meeting these criteria will be rejected.
In addition to the CV and covering letter, please email a completed copy of the Additional Details Form (Word document) to [Email Address Removed]. A blank copy of this form can be found at: https://www.nld-dtp.org.uk/how-apply.




Funding Notes

This is a 4 year BBSRC CASE studentship under the Newcastle-Liverpool-Durham DTP. The successful applicant will receive research costs, tuition fees and stipend (£15,009 for 2019-20). The PhD will start in October 2020. Applicants should have, or be expecting to receive, a 2.1 Hons degree (or equivalent) in a relevant subject. EU candidates must have been resident in the UK for 3 years in order to receive full support. Please note, there are 2 stages to the application process.

References

Veal et al (2004) A 2-Cys peroxiredoxin regulates peroxide-induced oxidation and activation of a stress-activated MAP kinase. Molecular Cell 15 129-139

Brown et al (2013) The thioredoxin peroxidase activity of a Prx promotes H2O2-signaling and oxidative stress resistance by oxidizing a thioredoxin family protein Cell Reports 5: 1425-35

Olahova et al (2008) A redox-sensitive peroxiredoxin that is important for longevity has tissue- and stress-specific roles in stress resistance. Proc Natl Acad Sci U S A. 105 19839-19844

Olahova and Veal (2015) A peroxiredoxin, PRDX-2, is required for insulin secretion andinsulin/IIS-dependent regulation of stress resistance and longevity Aging Cell 14:558-68

Tomalin et al (2016) Increasing extracellular H2O2 produces a bi-phasic response in intracellular H2O2with peroxiredoxin hyperoxidation only triggered once the cellular H2O2-buffering capacity is overwhelmed Free Radicals Biol. Med. (2016) 95:333-48

Tsuchiya Y et al., (2019) Redox Biology 38: Sep 5; Covalent Aurora A regulation by the metabolic integrator coenzyme A

Foulkes DM et al. (2018), Science Signaling 11:549; Covalent inhibitors of EGFR family protein kinases induce degradation of human Tribbles 2 (TRIB2) pseudokinase in cancer cells

Smith FD et al., (2017) Science 356: 1288. Local protein kinase A action proceeds through intact holoenzymes



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