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Generating a 3D Micro necroptosis induced Myocardial Infarction model

Project description

3D model for heart attack recovery

Cardiovascular disease is a global health crisis, with heart attacks causing over 80 % of related deaths. Myocardial infarctions (MI) lead to irreversible cardiomyocyte (CM) loss due to the heart’s inability to regenerate, making therapeutic drugs vital for recovery. However, drug development is costly, reliant on animal testing, and current human stem cell models are limited in accuracy and scalability. A challenge is the lack of viable 3D cardiac tissue models for testing therapies. Supported by the Marie Skłodowska-Curie Actions programme, the MiniMI project will create a 3D human-induced pluripotent stem cell (hPSC) model. Featuring an inducible ‘kill switch’ to mimic localised MI and integrated macrophages for realism, MiniMI will advance cardiac research, enabling precise drug screening and regeneration studies.

Objective

Cardiovascular disease remains one of the leading causes of death worldwide, with more than 4 out of 5 of these due to heart attacks. Following a myocardial infarction (MI) the loss of cardiomyocytes (CMs) is irreparable due to their non-proliferative state. Following a MI one of the most promising forms of recovery is using therapeutic drugs. Since generating a new drug requires considerable amounts of money and animal testing there is a need for alternative models such as human induced pluripotent stem cell (hPSC) models. hPSCs provide an excellent platform to model cardiac disease, although 2D models are too immature and currently 3D models are not viable for screening of therapeutic compound libraries.
To solve this, I aim to implement a 'kill switch' in a subpopulation of a 3D cardiac tissue, that when triggered will induce necroptosis in the population, simulating a localized heart attack. Integrating macrophages will improve the physiological relevance and cTnT-FUCCI CMs will be used to monitor CM proliferation.
To generate this innovative, dependable, inducible model of MI using hiPSCs, the project is divided into 3 achievable goals.
1. Generate a hPSC cell line with inducible kill switch system
2. Integrate macrophages into microtissues, induce the kill switch, investigate response to localized cell death and cellular changes producing a scRNA-Seq timeline
3. Incorporate cTnT-FUCCI cardiomyocytes to investigate cardiac regenerative therapies
I will receive state-of-the-art genetic modification training to generate the cell line (Goal 1), immune cell generation and integration (Goal 2) and bioinformatic study to identify key pathways identified through scRNA-Seq data generated from the MiniMI model to trial cardiac regenerative compounds (Goal 3). This project will not only generate a reliable model of MI capable for screening of cardioprotective compounds, but also a malleable model suitable for easy adaptation to other researchers interests.

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HORIZON-TMA-MSCA-PF-EF - HORIZON TMA MSCA Postdoctoral Fellowships - European Fellowships

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(opens in new window) HORIZON-MSCA-2023-PF-01

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Coordinator

ACADEMISCH ZIEKENHUIS LEIDEN
Net EU contribution

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€ 187 624,32
Address
ALBINUSDREEF 2
2333 ZA Leiden
Netherlands

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Activity type
Higher or Secondary Education Establishments
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Total cost

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