Project Details
Projekt
Targeting the Interstitium to Alter Fibrotic Remodelling in the Heart in vivo
Subject Area
Cardiology, Angiology
Term
since 2026
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 564978926
Until recently, the ECM was mainly regarded as a structural tissue component that defines the microenvironment of cells, influences the shape and strength of tissues, and acts as a substrate for cell migration. In recent years, there has been wider recognition of the cell-instructing function of the ECM as a mediator of cell-cell communications. These communications are mediated by either intact ECM proteins or proteolytically generated fragments called matrikines. However, the role of the ECM in mediating interstitial remodeling in cardiac lesions continues to be overlooked. Here, we aim to investigate the functions of the ECM in mediating cell–cell communication after MI, and to use this knowledge to develop ECM-targeted therapies that target the infarcted interstitium and remodel cardiac fibrosis. In particular, we will study the influence of ECM proteases and protease inhibitors on the modulation of the ECM and matrikines released in the diseased microenvironment, and thus their signalling and biological effects on various cell types. We will characterize the ECM protease ADAMTS-7, which is associated with the risk of coronary artery disease and MI, as well as other ECM-related proteases. Recent studies demonstrated that ADAMTS-7 mediates its effects on chronic cardiovascular inflammation via degradation or proteolytic modification of the ECM components SVEP1 and TIMP1. The degradation of SVEP1 by ADAMTS-7 modulates the recruitment of inflammatory cells from the blood via activation of EC. In the heart, ADAMTS-7 is expressed in CM during homeostasis, while its substrates are expressed by different cell types, particularly mural cells, EC, FB (for TIMP1), and FB and adipocytes (for SVEP1). While this illustrates the hetero-cellular sources of ADAMTS-7 and its substrates, the effects of cardiac ECM remodeling on these diverse cell types have not yet been described. In vitro assays and in vivo experiments using knockout mice and targeted delivery of ADAMTS-7-related molecules (e.g. inhibitors, substrates) will be used to clarify ECM-centered mechanisms of hetero-cellular communication. Using our expertise in protein engineering, targeted delivery of ADAMTS-7 and related proteins will be achieved through recombinant fusion to antibody fragments that target fibrin, fibronectin, or fibrillar collagens in cardiac lesions. In addition to being used as tools to modulate the inflamed cardiac interstitium, these approaches may hold therapeutic potential for fibrotic remodeling after MI.
DFG Programme
Research Units
