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The repair of damaged tissue by mitochondrial transplantation.

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  • Full or part time
    Dr Richard Southworth
    Dr T Eykyn
  • Application Deadline
    Applications accepted all year round

Project Description

Mitochondrial injury and mitochondrial dysfunction are central to numerous diseases, from myocardial infarction to stroke, neurogenerative diseases, inborn errors of metabolism, and drug toxicity. While efforts to prevent or reverse mitochondrial dysfunction pharmacologically continue, there is tantalising evidence in the literature that damaged mitochondria could actually be replaced by transplantation.

This is a nascent field, and the mechanisms underlying mitochondrial therapy are poorly understood, but recent reports demonstrate tissue salvage by infusion of isolated exogenous (or endogenous) mitochondria in preclinical models of stroke, acute lung injury, Parkinson’s disease and cardiac ischemia (preclinically and clinically in children). It appears that isolated mitochondria are not allergenic, and while they have been demonstrated protective when delivered by local tissue injection, they can also enter tissues even when injected systemically and may actively enter cells by a macropinocytotic process (which might be exploited to enhance targeting to damaged tissues).

In our laboratories we use isolated perfused rodent hearts to develop molecular imaging technologies to report non-invasively on biological processes utilizing PET, SPECT and NMR spectroscopy and MR imaging. To test and validate our novel imaging agents, we use these experimental setups to provide us with a physiologically relevant model over which we have complete control (in terms of oxygenation, energy substrate availability, drug administration etc.), allowing us to study the effects of ischaemia, drug toxicity and abnormal metabolic states, with real-time readouts of cardiac functional response. In this project, we will use these experimental models and our molecular imaging technologies to track the fate of radioactively labelled mitochondria once injected into the heart (and/or systemically into the body), and determine whether (and how) transplanted mitochondria can rescue vulnerable tissue after myocardial infarction, drug toxicity etc. We will combine these unique platforms to develop, optimise and validate the potential for mitochondrial transplantation to rescue damaged myocardium, and look for opportunities for translation of the technology to applications in other disease processes.

This project will train a biological scientist in the skills that they need for a career in the imaging sciences and instill in them the mindset required to be able to design and carry out careful and robust validation and characterisation work. While admittedly ambitious, this project will expose the student to a very large interdisciplinary team of academics, from whom they will acquire the surgical skills, animal husbandry and handling, biological assay development and histology skills that most post-doctoral biologists have, but they will be embedded in a department and a group where they will also learn about concepts in radiotracer design and evaluation, radionuclide imaging using PET and SPECT, data acquisition and pharmacokinetic modelling, Nuclear Magnetic Resonance and metabolomics. As such, we intend to educate and train a uniquely skilled, useful and versatile imaging scientist.


Funding Notes

We are currently seeking funding for this project, and it is currently under consideration for inclusion by several London-based doctoral training centres. Potential applicants are advised to contact the primary supervisor by email ([Email Address Removed]) to discuss their application and the current status of the studentship.

References

Hayakawa, K. et al. Transfer of mitochondria from astrocytes to neurons after stroke. Nature 535, 551-555, doi:10.1038/nature18928 (2016).
Islam, M. N. et al. Mitochondrial transfer from bone-marrow-derived stromal cells to pulmonary alveoli protects against acute lung injury. Nature medicine 18, 759-765, doi:10.1038/nm.2736 (2012).
Shi, X., Zhao, M., Fu, C. & Fu, A. Intravenous administration of mitochondria for treating experimental Parkinson's disease. Mitochondrion 34, 91-100, doi:10.1016/j.mito.2017.02.005 (2017).
Masuzawa, A. et al. Transplantation of autologously derived mitochondria protects the heart from ischemia-reperfusion injury. American journal of physiology. Heart and circulatory physiology 304, H966-H982, doi:10.1152/ajpheart.00883.2012 (2013).
Dhanjal, T. S. et al. Trapped Platelets Activated in Ischemia Initiate Ventricular Fibrillation. Circulation: Arrhythmia and Electrophysiology, doi:10.1161/circep.113.000591 (2013).
Handley, M. G. et al. Cardiac hypoxia imaging: second generation analogues of 64Cu-ATSM. J.Nucl.Med. 55, 488-494 (2014).
Medina, R. A. et al. 64Cu-CTS: A Promising Radiopharmaceutical for the Identification of Low-Grade Cardiac Hypoxia by PET. Journal of nuclear medicine : 56, 921-926, doi:10.2967/jnumed.114.148353 (2015).



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