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  Unravelling mechanisms of drug-induced myocarditis using human cardiovascular-chip models integrated with immune cells


   Blizard Institute

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  Dr Y Y Lin, Dr J Gautrot  No more applications being accepted  Funded PhD Project (UK Students Only)

About the Project

The 4-year PhD project aims to address an important and challenging knowledge gap concerning new therapeutic modalities, such as monoclonal antibodies and cell therapies, that can potentially induce cardiac toxicity in the clinic (i.e., inflammatory cardiomyopathy and myocarditis). To better understand mechanisms underlying immune-mediated cardiotoxicity, there is a significant need to develop human-relevant microphysiological systems to model drug-mediated immune responses in the heart. The successful candidate will receive first-class training from the Queen Mary University of London (QMUL) supervisors at the state-of-the-art biofabrication lab to assemble microvascularised cardiac tissues in microfluidic chips. In addition, the student will receive training by supervisors at AstraZeneca (Cambridge, UK), and will gain expertise in building immune-competent models for drug safety applications. Importantly, the supervisory team have complementary expertise to train the PhD student to tackle the intellectual challenges in the project.

Additionally, the successful candidate will attend the yearly ITTP residential toxicology training course, and will have access to the MRC Toxicology Unit’s Masterclass seminar series. QMUL offers an outstanding research environment for this PhD studentship, with strengths in medicine, science, and engineering. In the 2021 Research Excellence Framework, the university was ranked 7th in the country for research quality. The collaboration between QMUL and the industrial partner will ensure that the student will be exposed to both organisations’ vibrant and inclusive research environments. Furthermore, during the placement at the industrial site, the student will have the opportunity to learn more about the entire drug development process and build expertise in safety pharmacology in the pharmaceutical industry. 

Overall, the student will benefit from the interdisciplinarity of the project and the work undertaken at both the QMUL and industrial sites. Importantly, the knowledge gained during the PhD project may provide new insights into cardiovascular safety in drug development.

This award is based on the 2023/24 MRC UKRI inside London stipend guidance of: £20,622 per annum, fees for university registration of £4,712 per annum, £5,000 consumables per annum. The stipend and university registration fees are to be adjusted annually, as per UKRI recommendations, in line with the GDP deflator. Award value for 4 years: £121,420.

Eligibility requirements:

  • Applicants must hold a 1st class or 2:1 degree in life, biomedical or bioengineering sciences. With a life-sciences degree, maths, statistics or computing modules at A-Level or above are desirable.
  • Skills and knowledge matching the proposed area of doctoral research (Cardiovascular and Immunology)
  • High motivation and a passion for research.
  • To be eligible for full funding candidates will need to demonstrate that they have Home fee status.
  • Evidence of proficiency in English language skills.
  • Able to start by October 2024

APPLY HERE: IPP login screen (qmul.ac.uk)


Biological Sciences (4) Mathematics (25) Medicine (26)

Funding Notes

The MRC Integrative Toxicology Training Partnership (ITTP) is a prestigious and highly competitive national PhD training programme for capacity building in Toxicology and related disciplines. The matched funding from the industrial partner per year is expected to cover £3K for experimental work and £2K stipend top-up contribution, totalling £5K per year. Placement travel (equivalent of the duration of 3 months total throughout the project) costs are part of the in-kind contribution from the industrial partner and will cover tailored visits for the student’s placement within the industrial site.

References

1. Di Cio, S., Haddrick, M. and Gautrot, J. E. (2023) Vascularised Cardiac Spheroids-on-a-Chip for Testing the Toxicity of Therapeutics. bioRxiv. https://doi.org/10.1101/2023.01.20.524970
2. Varricchi G, Galdiero MR, Tocchetti CG. Cardiac Toxicity of Immune Checkpoint Inhibitors: Cardio-Oncology Meets Immunology. Circulation. 2017;136:1989-1992. doi: 10.1161/CIRCULATIONAHA.117.029626
3. Baik AH, Oluwole OO, Johnson DB, Shah N, Salem JE, Tsai KK, Moslehi JJ. Mechanisms of Cardiovascular Toxicities Associated With Immunotherapies. Circ Res. 2021;128:1780-1801. doi: 10.1161/CIRCRESAHA.120.315894
4. Zhu H, Galdos FX, Lee D, Waliany S, Huang YV, Ryan J, Dang K, Neal JW, Wakelee HA, Reddy SA, et al. Identification of Pathogenic Immune Cell Subsets Associated With Checkpoint Inhibitor-Induced Myocarditis. Circulation. 2022;146:316-335. doi: 10.1161/CIRCULATIONAHA.121.056730
5. Ahmed SM, Shivnaraine RV, Wu JC. FDA Modernization Act 2.0 Paves the Way to Computational Biology and Clinical Trials in a Dish. Circulation. 2023;148:309-311. doi: 10.1161/CIRCULATIONAHA.123.065585
6. Leung CM, de Haan P, Ronaldson-Bouchard K, Kim G-A, Ko J, Rho HS, Chen Z, Habibovic P, Jeon NL, Takayama S, et al. A guide to the organ-on-a-chip. Nature Reviews Methods Primers. 2022;2:33. doi: 10.1038/s43586-022-00118-6
7. Ramamurthy RM, Atala A, Porada CD, Almeida-Porada G. Organoids and microphysiological systems: Promising models for accelerating AAV gene therapy studies. Front Immunol. 2022;13:1011143. doi: 10.3389/fimmu.2022.1011143
8. Archer CR, Sargeant R, Basak J, Pilling J, Barnes JR, Pointon A. Characterization and Validation of a Human 3D Cardiac Microtissue for the Assessment of Changes in Cardiac Pathology. Sci Rep. 2018;8:10160. doi: 10.1038/s41598-018-28393-y
9. Yang L, Han Y, Jaffre F, Nilsson-Payant BE, Bram Y, Wang P, Zhu J, Zhang T, Redmond D, Houghton S, et al. An Immuno-Cardiac Model for Macrophage-Mediated Inflammation in COVID-19 Hearts. Circ Res. 2021;129:33-46. doi: 10.1161/CIRCRESAHA.121.319060
10. Ehlers H, Nicolas A, Schavemaker F, Heijmans JPM, Bulst M, Trietsch SJ, van den Broek LJ. Vascular inflammation on a chip: A scalable platform for trans-endothelial electrical resistance and immune cell migration. Front Immunol. 2023;14:1118624. doi: 10.3389/fimmu.2023.1118624