Project Details
Projekt
Repair and adaptation in acute myocardial infarction and chronic heart failure
Applicant
Professor Dr. Kai Christoph Wollert
Subject Area
Cardiology, Angiology
Term
from 2016 to 2020
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 286251789
Acute myocardial infarction triggers an inflammatory reaction thatleads to the necrotic area being replaced with vascularizedgranulation tissue and eventually a scar. The development of heartfailure after myocardial infarction depends, in part, on the quality ofthis wound healing response. In the failing heart, inflammatory cellscontrol important aspects of left ventricular remodeling, includingcardiomyocyte hypertrophy and apoptosis. In both situations,inflammatory cell-derived, paracrine-acting, reparative and(mal)adaptive growth factors are thought to play critical roles and toprovide new therapeutic opportunities. We recently identified a newgrowth factor in a bioinformatic secretome analysis in bone marrowcells from patients with acute myocardial infarction: Brick1, a 75amino acid polypeptide that is highly conserved in mice and humans.Brick1 is known to promote actin polymerization as an integral part ofthe intracellular WAVE protein complex. We believe that Brick1 canalso be released from myeloid cells (neutrophils, monocytes,macrophages) and act as a growth factor. We have shown thatextracellular Brick1 mediates pro-angiogenic, cardiomyocyte-protectiveand anti-hypertrophic effects in cell culture. We postulatethat extracellular Brick1 stimulates repair and adaptation aftermyocardial infarction and in heart failure. In the second fundingperiod, we propose to investigate Brick1’s endogenous function, itsmechanisms of action, and its therapeutic potential. Using loss-of-function(conditional knockout in myeloid cells, neutralizing Brick1antibody) and gain-of-function approaches (conditionaloverexpression in inflammatory cells), we want to examine Brick1’srole in acute myocardial infarction (ischemia-reperfusion model) andcardiac hypertrophy/failure (transverse aortic constriction). We want toanalyze how Brick1 is released from myeloid cells and how itmediates its biological effects (phosphoproteome analysis andidentification of the putative receptor). We aim to develop aquantitative mass spectrometry assay to measure Brick1 in thecirculation of mice and patients with acute myocardial infarction orheart failure. Finally, we want to explore Brick1’s therapeutic potentialin mice with acute myocardial infarction, heart failure, or cardiogenicshock.
DFG Programme
Clinical Research Units
