Project Details
Projekt
P7: Differential silencing of key collagen maturation steps as a way to control diffuse and focal interstitial fibrosis of the heart
Subject Area
Cardiology, Angiology
Anatomy and Physiology
Cell Biology
Anatomy and Physiology
Cell Biology
Term
since 2026
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 564978926
The composition of the extracellular matrix (ECM) critically determines cardiac structure and function, shaped by the balance between its synthesis, maturation, and degradation. The enzymes lysyl hydroxylase 2 (LH2, encoded by Plod2) and lysyl oxidase (LOX) govern ECM maturation by catalysing distinct lysine modifications in collagen that promote fibrillar cross-linking. The type and degree of cross-linking define collagen stability and degradability, thereby influencing both the development and reversibility of cardiac fibrosis. To investigate these mechanisms, we will employ cell-specific, inducible deletion of Plod2 and Lox in mouse models developing focal replacement and diffuse interstitial fibrosis. These pathological forms of interstitial remodeling will be induced by permanent occlusion of the left anterior descending artery (LADx) or transverse aortic constriction (TAC), respectively. We hypothesize that LH2- and LOX-dependent regulation of ECM composition, cross-linking, and degradability differs between these two types and across the time course of post-injury healing, thereby defining the potential to reverse adverse fibrotic outcomes. In WP1, we will use a reciprocal approach - enzyme excess through recombinant supplementation and cell-specific genetic ablation - to directly link enzyme-specific modulation of collagen cross-linking to ECM stability and degradability. Methods established in WP1 will relate LOX- and LH2-dependent collagen modification to contractile, biomechanical, and biochemical properties in vitro. WP2 will delineate the spatiotemporal organization of ECM cross-linking during diffuse interstitial (post-TAC) and focal replacement fibrosis (post-LADx), identifying how ECM matures into rigid, non-degradable scar tissue and whether critical turning points can be monitored via circulating biomarkers. WP3 will analyze cell-specific, inducible Plod2 and Lox deletions at early and late phases of remodeling, defining the roles of LH2 and LOX and allowing direct comparison between MI- and pressure overload-induced fibrosis. WP4 will determine whether reduced LH2- or LOX-mediated cross-linking increases ECM degradability and improves cardiac function. Overall, the project will characterize ECM remodeling in diffuse (TAC) and focal (LADx) fibrosis, integrating ECM production, maturation, and degradation. These findings will complement and synergize with the FOR consortium by advancing mechanistic insight into how the cardiac interstitium governs fibrosis progression and dysfunction.
DFG Programme
Research Units
