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Investigating the mechanisms and consequences of ANP aggregation in ageing; a computational and experimental approach

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  • Full or part time
    Dr J Madine
    Prof D Rigden
    Prof M Taggart
  • 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

Natriuretic peptides (NPs) are structurally related bioactive peptides conserved in vertebrates that are important regulators involved in fluid volume and water/salt balance. NPs are used as biomarkers for cardiovascular diseases such as stroke, coronary artery disease, myocardial infarction and heart failure. ANP is the main component of atrial amyloid deposits, an age-related amyloidosis. However, the mechanisms underlying the process of ANP aggregation are not understood. It is unclear if the pathological process associated with atrial amyloid deposition is due to a gain of toxicity from the amyloid deposits (or the aggregation process through a pro-inflammatory response) or due to a loss of function of ANP to perform its native role of vasodilation/fluid maintenance and signalling. This important aspect of understanding the mechanisms underlying the process of ANP aggregation will be investigated during the rotation at the second institute.

This project will employ a combined computational and experimental structural biology approach to probe the structural properties of ANP and additional factors known to be associated with ANP amyloid deposits to identify key features responsible for initiation of aggregation.

This joint project will provide multi-disciplinary training in bioinformatics, biochemical and biophysical techniques and cell signalling.

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.

Informal enquiries may be made to [Email Address Removed]

Funding Notes

This is a 4 year BBSRC 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

Oxidative stress alters the morphology and toxicity of aortic medial amyloid. Biophys J, 109, 2363-2370 (2015)

Probing Medin Monomer Structure and its Amyloid Nucleation Using 13C-Direct Detection NMR in Combination with Structural Bioinformatics. Sci Reports 7, 45224 (2017)

Large scale ab initio modeling of structurally uncharacterized antimicrobial peptides reveals known and novel folds. Proteins, 86(5):548-565 (2018)

Inhibition of Inflammatory Changes in Human Myometrial Cells by Cell Penetrating Peptide and Small Molecule Inhibitors of NFκB. Front Immunol. 9: 2966 (2018)

Amyloidogenic medin induces endothelial dysfunction and vascular inflammation through the receptor for advanced glycation endproducts. Cardiovasc Res, 113, 1389–1402 (2017)

Applications of contact predictions to structural biology. IUCrJ, 4(3):291-300 (2017)

From Protein Structure to Function with Bioinformatics, second edition. Springer, Dordrecht (2017)

Depletion of myofibril-associated proteins using selective protein extraction as a tool in cardiac proteomics. Methods in Mol. Biol. (2017)

Estrogenic vascular effects are diminished by chronological ageing. Sci Rep. 7: 12153 (2017)

The Generation of a Comprehensive Spectral Library for the Analysis of the Guinea Pig Proteome
by SWATH-MS. Proteomics 19: e1900156 (2019)



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