Investigating the molecular mechanisms and consequences of ANP aggregation for cardiovascular disease; a computational and experimental approach

Description

Atrial natriuretic peptide (ANP) is a cardiovascular hormone synthesised and secreted by myocytes in the atrial wall where it regulates atrial blood volume and vasodilation. The cleavage of its precursor by corin enzyme results in ANP, a disulphide-stabilised 28 residue peptide, and the 98 residue remainder NT-proANP.

ANP is the main component of isolated atrial amyloidosis (IAA), an age-related amyloidosis associated with Congestive Heart Failure (CHF). Amyloid deposits also contain β-ANP (a poorly characterised disulphide-linked dimer) and NT-proANP. It is unclear if the pathological process associated with IAA is due to a gain of toxicity from the amyloid deposits/aggregation process or due to a loss of function of ANP to perform its native role of vasodilation/fluid maintenance and signalling.

The first part of this project will investigate the molecular mechanisms of ANP aggregation, the involvement of additional factors such as NT-proANP and membranes, and the role of the disulphide bond in ANP stability. We will use Molecular Dynamics (MD) to explore the conformational ensembles of ANP and NT-proANP in conjunction with structure-based amyloidogenicity prediction in order to probe how these molecules reach a state in which aggregation is initiated. The project will involve close collaboration with the Computational Biology group at STFC, who will provide guidance in simulation methods, including enhanced sampling and free energy estimation.

Experimentally, ANP aggregation will be probed and the role of disulphide bonds and additional factors investigated to complement the computational aspect of the project. Mutant versions of ANP (guided by computational analysis and a known natural variant associated with increased heart disease) will be made and tested for alterations in stability and aggregation.

The project is suited to a student with at least a good B.Sc. Upper Second in Biological or Life Sciences (particularly biochemistry and/or bioinformatics).

Please note this application will close once a suitable candidate is found. Early applications are encouraged.

To apply please click here

Availability

Open to students worldwide

Funding information

Self-funded project

The project is open to both European/UK and International students. It is UNFUNDED and applicants are encouraged to contact the Principal Supervisor directly to discuss their application and the project.

Assistance will be given to applications who are applying to international funding schemes.

The successful applicant will be expected to provide the funding for tuition fees and living expenses as well as research costs of £3000 per year.

A fee bursary may be available for well qualified and motivated applicants.

Details of costs can be found on the University website.

Supervisors

References

Davies, H.A., Rigden, D.J., Phelan, M.M., Madine, J. Probing Medin Monomer Structure and its Amyloid Nucleation Using 13C-Direct Detection NMR in Combination with Structural Bioinformatics. Sci Rep, 2017. 7:45224. 

Millucci, L., et al., Different Factors Affecting Human ANP Amyloid Aggregation and Their Implications in Congestive Heart Failure. PLoS ONE, 2011. 6:e21870.

Louros, N.N., et al., An N-terminal pro-atrial natriuretic peptide (NT-proANP) ‘aggregation-prone’ segment involved in isolated atrial amyloidosis. FEBS Letters, 2014. 588:52-57.

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