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Harnessing stem cells to develop regenerative therapies for childhood heart disease.


Project Description

LABORATORY OVERVIEW:

The Cardiac Regeneration Laboratory is seeking highly motivated PhD students to work on a project related to understanding the underlying causes of congenital heart disease and developing novel regenerative therapies. We tailor PhD projects towards the interests of the student with an emphasis on pluripotent stem cell models of cardiac development and regeneration. Our laboratory is based at the Murdoch Children’s Research Institute, which is the largest child health research organisation in Australia. Our research is integrated within a leading Stem Cell Medicine program with strong links to clinician-scientists within the Royal Children’s Hospital on the Melbourne Children’s campus. We are well supported by core research infrastructure including iPS derivation and editing core facilities, high-content imaging and advanced microscopy platforms, biobanking and clinical genomics. PhD students are enrolled through the Department of Physiology at The University of Melbourne. According to The World University Rankings, The University of Melbourne is ranked 9th globally in Clinical, Pre-Clinical and Health.

AVAILABLE PROJECT:

"Modelling heart disease in a dish using patient-derived stem cells and drug screening."

One key area of our heart research focuses on creating stem cells from patients with congenital heart disease and recreating their heart tissue in our laboratories. This allows us to recreate and study their disease more closely – this method of research is called disease modelling. If we are able to determine a genetic cause for the disease through studying a patient’s tissue in the laboratory, we now have the gene editing capability and technology to correct mutations found in that patients’ genome. By comparing a patient’s genetically mutated and corrected cell lines, we are able to better understand a disease’s cause and progression, which informs our understanding of any potential preventative measures, tests for that disease, developing new treatments and hopefully cures. We are also investigating whether iPS-derived cardiac organoids can be used to screen for drugs that promote regeneration of cardiomyocytes in children with heart disease.

This project will develop iPS disease models of congenital heart disease for high-content screening to discover novel disease mechanisms and potential drug targets. PhD students will develop skills in iPS cell culture and differentiation including 3D organoids, gene editing, microscopy, transcriptomics/proteomics and cardiomyocyte physiology. High-content screening will be facilitated by the development of genetically encoded reporters to assess calcium handling, electrophysioloigcal properties, cell cycle status and biomechanical forces in iPS-derived cardiomyocytes. Candidate genes/pathways identified in the screen will be further validated and characterised using sophisticated genetic, biochemical and physiological approaches including gain/loss of function, contractility assays in 3D organoids and transcriptomics approaches (including single cell profiling).

Interested students are invited to send their CV and academic transcripts to A/Prof Enzo Porrello and Dr David Elliott.

Funding Notes

Funding is available for a PhD stipend for this project ($30,000 tax-free living allowance in accordance with current University of Melbourne Graduate Research Scholarship allowance).

References

1. Mills RJ, Titmarsh DM, Koenig X, Parker BL, Ryall JG, Quaife-Ryan GA, Voges HK, Hodson MP, Ferguson C, Drowley L, Plowright AT, Needham EJ, Wang Q, Gregorevic P, Xin M, Thomas WG, Parton RG, Nielsen LK, Launikonis BS, James DE, Elliott DA, Porrello ER*, Hudson JE*. Functional Screening in Human Cardiac Organoids Reveals a Metabolic Mechanism for Cardiomyocyte Cell Cycle Arrest. Proc Natl Acad Sci USA. 2017. 14(40):E8372-E8381 *Co-corresponding. [Impact Factor = 9.661, Citations =13]

2. Quaife-Ryan GA, Sim CB, Ziemann M, Kaspi A, Rafehi H, Ramialison M, El-Osta A, Hudson JE, Porrello ER. Multi-cellular Transcriptional Analysis of Mammalian Heart Regeneration. Circulation. 2017. 136(12):1123-1139. [Impact Factor = 19.309, Citations = 20]


4. Porrello ER, Mahmoud AI, Simpson E, Hill JA Richardson JA, Olson EN, Sadek H. Transient regenerative potential of the neonatal mouse heart. Science. 2011. 331(6020): 1078-80. [Impact Factor = 37.205, Citations = 1188]

5. Elliott DA, Braam SR, Koutsis K, Ng ES, Jenny R, Lagerqvist EL, Biben C, Hatzistavrou T, Hirst CE, Yu QC, Skelton RJP, Ward-Van Oostwaard D, Lim SM, Khammy O, Li X, Hawes SM, Davis RP, Goulburn AL, Passier R, Prall OWJ, Haynes JM, Pouton CW, Kaye DM, Mummery CL, Elefanty AG, Stanley EG. NKX2-5(eGFP/w) hESCs for isolation of human cardiac progenitors and cardiomyocytes. Nat Methods. 2011;8(12):1037-40. [Impact Factor = 25.062, Citations = 291]

6. Anderson DJ, Kaplan DI, Bell KM, Koutsis K, Haynes JM, Mills RJ, Phelan DG, Qian EL, Leitoguinho AR, Arasaratnam D, Labonne T, Ng ES, Davis RP, Casini S, Passier R, Hudson JE, Porrello ER, Costa MW, Rafii A, Curl CL, Delbridge LM, Harvey RP, Oshlack A, Cheung MM, Mummery CL, Petrou S, Elefanty AG, Stanley EG, Elliott DA. NKX2-5 regulates human cardiomyogenesis via a HEY2 dependent transcriptional network. Nat Commun. 2018;9(1):1373. doi: 10.1038/s41467-018-03714-x. [Impact Factor = 12.353, Citations = 1]

7. Phelan DG, Anderson DJ, Howden SE, Wong RC, Hickey PF, Pope K, Wilson GR, Pebay A, Davis AM, Petrou S, Elefanty AG, Stanley EG, James PA, Macciocca I, Bahlo M, Cheung MM, Amor DJ, Elliott DA*, Lockhart PJ. ALPK3-deficient cardiomyocytes generated from patient-derived induced pluripotent stem cells and mutant human embryonic stem cells display abnormal calcium handling and establish that ALPK3 deficiency underlies familial cardiomyopathy. Eur Heart J. 2016;37(33):2586-90. [Impact Factor = 23.425, Citations = 11] *Senior Author

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