After a heart attack, growth of new lymphatic vessels in the heart influences how the immune system responds both to the initial injury and to later stages of established heart failure.
This project will perform screens to identify new compounds that trigger the production of helpful signals supporting lymphatic growth immediately after heart attack and during stages of established heart failure.
Challenges
Target discoveryPeople
- Paul Riley
- Mauro Giacca
- Christophe Ravaud
Organisations
- University of Oxford
- King's College London
In depth
Myocardial infarction (MI) induces cardiac muscle death and its subsequent replacement by a non-contractile fibrotic scar, which leads to heart failure. Current treatments restore blood flow and assist with cardiac workload. However, none are regenerative and clinical trials using stem cell-based approaches have been disappointing. We have shown endogenous growth of the cardiac lymphatic system following MI and further stimulation with VEGFC-C156S, resolves the immune response and improves cardiac function. Even though this growth induction sounds promising, the short half-life and broad target profile of VEGFC-C156S makes it sub-optimal for clinical use.
To find further cardiac lymphatic system regeneration targets (mRNA, miRNA and siRNA that act as inducers of lymphangiogenesis) we are going to use our miniaturised sprouting assay in an unbiased screen. The positive targets will be validated in a micro-vessel-leukocyte adhesion and ingression assay and 3D microfluidic organ-on-a-chip with our collaborators (Ayman Al Haj Zen, Hamad Bin Khalifa University) for their ability to specifically promote monocyte/macrophage and dendritic cell/T-cell ingression. The final hits will be subjected to validation in our in vivo MI/HF models with intravital imaging and ECHO/MRI for functional assessment.