TraFICa · Transcription Factor-mediated Induction of Cardiomoycyte proliferation.

Heart failure is a major global public health problem affecting over 23 million patients worldwide. There are no effective therapies for heart failure that regenerate the damaged heart muscle following injury such as a myocardial infarction. The adult mammalian heart has an extremely limited intrinsic capacity for regeneration due to the fact that mature cardiomyocytes are unable to proliferate. To date, attempts to re-induce proliferation in mature cardiomyocytes of the adult heart have not yet been translated into the human clinical context. Much remains to be learned about molecular mechanisms controlling cardiomyocyte proliferation in humans if the therapeutic potential for cardiac regeneration is to be realised. With my extensive training and expertise in molecular and stem cell biology I plan to generate and exploit an innovative live cell cycle reporter-based screening platform to identify Transcription Factors (TFs) that can be induce cardiomyocyte proliferation. The three major objectives of this research proposal are: 1. Develop a high-content screening system to monitor cardiomyocyte proliferation in 3D human cardiac organoids, which will then be used to:2. Identify (combinations of) TFs that drive the human cardiomyocyte cell cycle.3. Assess the therapeutic potential of TF activation for cardiac regeneration in a pre-clinical human cardiac model system. I will receive extensive training in the ex vivo cardiac tissue culture system (objective 3), which will complement my proven expertise in the generation of (genetically modified) 3D cardiac organoids and knowledge on cell cycle regulation (objective 1 & 2). Altogether, the tool development, results and training obtained during this project will put me in the forefront of the cardiac regenerative field.