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Nanoparticle-based delivery to the heart for treatment of inherited cardiac conditions


School of Chemistry

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Prof R O'Reilly , Dr K Gehmlich , Dr A Pearce No more applications being accepted Funded PhD Project (UK Students Only)

About the Project

The Midlands Integrative Biosciences Training Partnership 3 (MIBTP2020) is a BBSRC-funded doctoral training partnership between the University of Warwick, University of Birmingham, University of Leicester, Aston University and Harper Adams University recruiting students for four-year studentships starting in Oct 2020. This innovative, interdisciplinary research training programme offers the opportunity to undertake a PhD in the fundamental understanding of, and application of functional nanomaterials to societal challenges, including energy, health, or emerging technologies. Our four-year integrated PhD programme begins with a structured year of training, giving you all the foundation skills necessary to prosper in your PhD research and beyond.

Healthy ageing in the Western world relies on healthy diet, sufficient exercise and avoiding risk factors such as smoking, alcohol consumption or environmental stressors, but is partly also defined by the genetic setup of an individual. For the majority of people, co-morbidities emerge with age. One prime example for an age-related cardiac co-morbidity is atrial fibrillation (AF), the most common cardiac arrhythmia. AF is prevalent in the aging population (affecting 7 in 100 over 65 years) and associated with a high risk of stroke and development of heart failure [1]. Insights into the molecular mechanisms of AF in pre-clinical studies have led to the identification of potential preventative agents, such as the inhibition of Ca2+ /calmodulin-dependent protein kinase II (CamKII) [2]. However, targeting of this enzyme appears currently not a viable preventative option, as inhibition of CamKII has detrimental effects on the brain and its memory functions. Specific targeting of CamKII inhibitors to the heart, but not to the brain, would be a pre-requisite for exploring CamKII inhibition as a therapeutic option for AF.

The aim of this studentship is therefore to engineer nanoparticles [3] allowing specific delivery of preventative agents to the heart. To achieve this, the student will work with an interdisciplinary team of supervisors consisting of chemists with significant experience in nanotechnology and drug delivery, and a biologist with expertise in inherited cardiac conditions, using world-class facilities at the University of Birmingham. Nanoparticles will be synthesised in the School of Chemistry and cardiomyocyte specificity achieved through the display of peptides, mimicking ligands which interact with cardiomyocyte-specific surface receptors. Cargos will initially include reporter genes or dyes and will evolve to therapeutic agents in the later stages of the project. The efficient targeting of nanoparticles will be tested in cardiac in vitro systems, making use of mouse primary atrial and ventricular cardiomyocytes and human induced pluripotent stem cell derived cardiomyocytes. This work will take place in the dedicated Institute of Cardiovascular Sciences. In the later stages of the project, the potential benefits of nano-particle delivery for preventative agents (e.g. CamKII inhibitors) will be assessed in a cellular model system of arrhythmia, making use of genome-edited induced pluripotent stem cell derived cardiomyocytes and electrophysiological read-outs.

Supervisory Team

Lead supervisor: Prof Rachel O’Reilly (School of Chemistry)
Co-supervisors: Dr Katja Gehmlich (MDS, Institute of Cardiovascular Sciences) and Dr Amanda Pearce (School of Chemistry)

Funding Notes

To check eligibility please see: https://warwick.ac.uk/fac/cross_fac/mibtp/pgstudy/phd_opportunities/application/#Eligibility

References

Insights into active targeting of nanoparticles in drug delivery: advances in clinical studies and design considerations for cancer nanomedicine. A. K. Pearce and R. K. O’Reilly, Bioconjugate Chem., 2019, 30, 9, 2300-2311, DOI: 10.1021/acs.bioconjchem.9b00456

Rauschenbach, M, Lawrenson, SB, Taresco, V, Pearce, AK & O'Reilly, RK 2020, 'Antimicrobial hyperbranched polymer-usnic acid complexes through a combined ROP-RAFT strategy', Macromolecular Rapid Communications. https://doi.org/10.1002/marc.202000190

Azad, A, Poloni, G, Sontayananon, N, Jiang, H & Gehmlich, K 2019, 'The giant titin: how to evaluate its role in cardiomyopathies', Journal of Muscle Research and Cell Motility, vol. 40, no. 2, pp. 159-167. https://doi.org/10.1007/s10974-019-09518-w

Ehsan, M, Kelly, M, Hooper, C, Yavari, A, Beglov, J, Bellahcene, M, Ghataorhe, K, Poloni, G, Goel, A, Kyriakou, T, Fleischanderl, K, Ehler, E, Makeyev, E, Lange, S, Ashrafian, H, Redwood, C, Davies, B, Watkins, H & Gehmlich, K 2018, 'Mutant Muscle LIM Protein C58G causes cardiomyopathy through protein depletion', Journal of Molecular and Cellular Cardiology, vol. 121, pp. 287-296. https://doi.org/10.1016/j.yjmcc.2018.07.248
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