REMAKIN · REstoring myocardial repair capacity via the modulation of MAcrophage-mediated cytoKINe secretion.
Horizon 2020 — Marie Skłodowska-Curie Actions
- Duration
- 2019-08-01 → 2021-07-31
- EU contribution
- €196,708
- Participants
- 1
- Scheme
- MSCA-IF-EF-ST
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Results in brief
REstoring myocardial repair capacity via the modulation of MAcrophage-mediated cytoKINe secretion.
Type-2 diabetes (T2D) is a chronic condition generating enormous healthcare costs. To make things worse, prevalence of T2D is increasing at an alarming rate worldwide. T2D is caused by peripheral insulin resistance (IR) and is associated with cardiovascular diseases and myocardial infarction (MI) in particular. Myocardial infarction triggers a sterile, innate inflammatory response essential for successful tissue repair and remodelling. Macrophages are innate inflammatory cells that play a strategic role by tightly controlling inflammation and orchestrating the remodelling of the infarcted heart through the secretion of immunomodulatory cytokines and by clearing the injured cardiac tissue from dead cells through a process called efferocytosis. In chronic inflammatory diseases such as Type-2 Diabetes (T2D), the immunomodulatory role of macrophages is impaired, leading to unchecked, chronic inflammation driving adverse tissue remodelling and the development of heart failure. However, the molecular mechanisms underlying the immunomodulatory function of macrophages and how they are affected during insulin resistance remains completely unknown. The objectives of the REMAKIN project are designed to improve our understanding on two critical points: how macrophages modulate inflammation in the infarcted heart and how T2D affects it.
Data: CORDIS, © European Union
Project objective
Type-2 diabetes (T2D) is a chronic condition strongly associated with cardiovascular diseases, mainly recurrent myocardial infarctions (MI), and generating enormous healthcare cost. Macrophages orchestrate the remodelling of the heart post-MI by efferocytosis-mediated cytokine secretion. Specifically, Mertk-mediated efferocytosis promotes vessel formation, tissue reperfusion and resolution of the inflammatory response via the secretion of the anti-inflammatory cytokines interleukin-10 (IL-10) and Vascular Endothelial Growth Factor-A (VEGF-A). In IR/T2D, efferocytosis-mediated cytokine secretion is impaired, leading to chronic inflammation, adverse post-MI remodelling, recurrent heart failure and excessive mortality. To date, the signalling and intracellular trafficking pathways leading to cytokines secretion are unknown, and the mechanisms of impairment during IR/T2D are unexplored. Previous therapeutic strategies focussed on repairing damaged tissue by injection of progenitor cells or modulating inflammation by cytokine injection, but both strategies gave disappointing results. In this proposal, I will define the mechanisms of efferocytosis-mediated cytokine secretion in macrophages, investigate their defects in IR/T2D and test a novel cell-based therapeutic strategy for improving recovery of T2D patients post-MI and preventing recurrence of cardiac events by restoring cytokine secretion in diabetic macrophages.
Original text from CORDIS.
Participants
- INSTITUT NATIONAL DE LA SANTE ET DE LA RECHERCHE MEDICALE · ParisCoordinatorFrance
Links
Data: CORDIS, © European Union