Kennedy Trust Prize Studentships
Promoting cardiac regeneration by targeting endogenous stem cells
Following acute myocardial infarction many patients develop heart failure as the injured muscle is replaced by fibrous tissues, resulting in survival rates of less than 50% at 5 years, which is worse than many cancers. The heart is capable of regeneration and we have identified a population of progenitor cells in the adult myocardium(1). However, clinical trials based on administration of stem cells to promote regeneration after myocardial infarction have largely failed, as have strategies targeting specific molecular pathways(2). Our long-standing interest in tissue injury has recently centred on alarmins, a group of structurally diverse endogenous mediators of innate and adaptive immunity that are rapidly released in response to injury(3). We have discovered that systemic administration of a single dose of the alarmin HMGB1 promotes regeneration of multiple tissues by transitioning resident CXCR4+ stem and progenitor cells to GAlert(4). This project will investigate the regenerative potential of HMGB1 following myocardial infarction, identify the target cell population and mechanisms of action with a view to developing a strategy that could potentially translate to the clinic.
The successful candidate will benefit from dual supervision by a surgeon scientist with a focus on translational medicine and a renowned authority on cardiac stem cells and myocardial regeneration. You will be based in the new, purpose built labs at The Kennedy Institute of Rheumatology, a world-leading centre in the fields of cytokine biology and inflammation, with a strong emphasis on clinical translation, and work closely with the Riley lab at Department of Physiology, Anatomy and Genetics. The project will use a combination of human samples and murine models. There is support available from post-doctoral scientists in our groups and lab managers to become proficient in cell and molecular biological techniques, including flow cytometry, mass cytometry, mass spectrometry, immunofluorescence, tissue culture, microscopy, in vivo imaging and animal disease models.
- Smart N, Bollini S, Dube KN, Vieira JM, Zhou B, Davidson S, Yellon D, Rieglar J, Price AN, Lythgoe MF, Pu WT, Riley PR. De novo cardiomyocytes from within the activated adult heart after injury. Nature. 2011;474(7353):640-4.
- Cahill TJ, Choudhury RP, Riley PR. Heart regeneration and repair after myocardial infarction: translational opportunities for novel therapeutics. Nat Rev Drug Discov. 2017.
- Chan JK, Roth J, Oppenheim JJ, Tracey KJ, Vogl T, Feldmann M, et al. Alarmins: awaiting a clinical response. J Clin Invest. 2012;122(8):2711-9.
- Lee G, Espirito Santo AE, Zwingenberger S, Vereneau E, Cai L, Vogl T, Feldmann M, Horwood N, Bianchi ME, Chan JK-K, Nanchahal J. HMGB1 accelerates the regeneration of multiple tissues by transitioning stem cells to GAlert. Science. 2017; under review.
Translational medicine and medical technology, cardiovascular sciences, developmental biology and stem cells, molecular cell and systems biology