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Inflammation in atrial fibrillation, heart failure and thrombosis: Exploring iron dysregulation and Dormant Microbes


Project Description

The most prevalent cardiovascular diseases are chronic and progressive in nature, and are all accompanied by chronic inflammation, which may be responsible for pathogenesis of the disease and its complications. These include atherosclerotic vascular disease, atrial fibrillation (AF) and heart failure. AF is the commonest heart rhythm disorder, associated with thromboembolism, thought to have a pathogenesis related to inflammation. Health failure is highly prevalent and a major cause of death and hospitalisation. Both these conditions all share significant features, such as increased inflammatory cytokines that have been linked to a prothrombotic tendency.

Taking a systems approach, Kell and Pretorius (2018) have previously hypothesised that the causes of such chronic inflammation could include (i) stress-induced iron dysregulation, and (ii) the latter’s ability to awaken dormant, non-replicating microbes with which the host has become infected. These microbes may shed small, but functionally significant proinflammatory molecules such as lipopolysaccharide and lipoteichoic acid. These can lead to a prothrombotic state, eg. the amyloidogenic clotting of blood, leading to cell death and the release of further proinflammatory molecules. Indeed, acute induction of anomalous and amyloidogenic blood clotting by molecular amplification of highly substoichiometric levels of bacterial lipopolysaccharide has been reported (Pretorius et al 2016). The same mechanism may apply in relation to the prothrombotic state in heart failure patients with associated AF.
This PhD will investigate predisposing risk factors that are closely associated with incident AF and its (prothrombotic) complications, ie. heart failure, sleep apnoea. Associated mechanisms such as prothrombotic indices and metabolomics will be studied.
There is an opportunity to join an AF research team that is globally recognised for AF research [http://bit.ly/2wJswe4].

The successfully appointed student would preferably have a background in biochemistry, systems biology or analytical science, and would have a particular interest in the analysis of ‘big data’ (for which training can be provided).

The Institute of Ageing and Chronic Disease is fully committed to promoting gender equality in all activities. In recruitment we emphasize the supportive nature of the working environment and the flexible family support that the University provides. The Institute holds a silver Athena SWAN award in recognition of on-going commitment to ensuring that the Athena SWAN principles are embedded in its activities and strategic initiatives.

A background in biochemistry, systems biology or analytical sciences is preferred with a particular interest in the analysis of ‘big data’ (for which training can be provided).

Start date would be by negotiation between the Supervisors and Student.

Informal enquiries to: Professor Gregory Lip
Professor Douglas Kell

To apply please send your CV and a covering letter to: Professor Lip with a copy to

Funding Notes

This would be an unfunded PhD studentship and annual £6000-12000 for research expenses may be required.

References

Kell DB, Pretorius E. No effects without causes: the Iron Dysregulation and
Dormant Microbes hypothesis for chronic, inflammatory diseases. Biol Rev Camb Philos Soc. 2018 Aug;93(3):1518-1557.

Khan AA, Lip GYH. The prothrombotic state in atrial fibrillation: pathophysiological and management implications. Cardiovasc Res. 2019 Jan 1;115(1):31-45.

Pretorius E, Mbotwe S, Bester J, Robinson CJ, Kell DB. 2016 Acute induction of anomalous and amyloidogenic blood clotting by molecular amplification of highly substoichiometric levels of bacterial lipopolysaccharide. J. R. Soc. Interface 13: 2016 0539. http://dx.doi.org/10.1098/rsif.2016.0539

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