Project Details
Projekt
Investigating the mechanisms of cardiomyocyte-mediated crosstalk in vascular cell remodeling and cellular stress - towards regenerative therapies
Subject Area
Pharmacology
Term
since 2024
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 549060740
Cardiovascular diseases (CVD) lead to 520 million people living with heart, circulatory problems and reduced life quality worldwide. The combination of therapies targeting cardiomyocyte stress along with pro-angiogenesis are considered to be highly promising from the clinical perspective. Mechanistically, the link between these processes needs to be solved, which forms the goal of the present proposal. We have previously described the relevance of Wnt activation in hypertrophic remodeling, which triggers (i) a cell-autonomous cardiomyocyte reprograming and (ii) cell-nonautonomous vascular developmental programs. These hearts showed upregulation of Insulin growth factor binding protein (IGFBP) 5. This upregulation was validated at the single cell resolution in cardiomyocytes, smooth muscle and mesothelial-epicardial like cells with concomitantly increased serum levels in mice and human failing heart. Endogenous activation of IGFBP5 expression in cardiomyocytes using the CRISPRa approach, was sufficient to increase serum levels and to trigger a transcriptional program involved in vascular cell development as well as inhibiting cellular stress and inflammation. We postulate that endogenous upregulation of IGFBP5 in the failing myocardium may be too late for inducing an effective reparative program. Based on our findings, we propose a crosstalk of cardiomyocyte and vascular cell lineages involving activation of vascular developmental and reparative programs along with cardiomyocyte protection effects, in which IGFBP5 may play a role. In this study, we aim to elucidate these mechanisms and to what extent they may contribute to the effective regeneration of vascular cells and protection of cardiomyocytes during human pathological processes. To achieve these aims, the present study consists of four work packages including (I) Elucidating the role of IGFBP5 in different microenvironments during maturation and in the adult healthy and diseased heart in vivo; (II) Elucidating IGFBP5 cell-autonomous effects and its autocrine and IGF-independent functions in human iPSC-derived cardiac cells; (III) Defining the cell-non-autonomous effects along with the mechanisms of IGFBP5 cellular transport and transcriptional actions in cardiac cell-to-cell communication as well as (IV) Elucidating the roles of IGFBP5 in cellular remodeling in the human heart niche. This project will provide insight into a well-characterized endogenous mechanism of cell remodeling in in vivo and in human models by applying transgenic technologies for transcriptional modulation in animal and hiPSC-based models, imaging, cellular electrophysiology and more important the use of patient´s derived material. This will allow to ultimately close the gap between basic and translational research and provide new concepts for therapeutic intervention.
DFG Programme
Research Grants
