Project Details
Projekt
P4 - Deciphering the interaction and functional patterns of GPCR autoantibodies
Subject Area
Rheumatology
Cardiology, Angiology
Clinical Immunology and Allergology
Pneumology, Thoracic Surgery
Cardiology, Angiology
Clinical Immunology and Allergology
Pneumology, Thoracic Surgery
Term
since 2026
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 552470287
Autoantibodies (Abs) targeting G protein-coupled receptors (GPCRs) are increasingly recognized as potent biomarkers, as well as drivers and modulators of receptor function. Studies on GPCR-specific Abs have indicated their ability to influence the intensity, localization, and composition of inflammation, thereby contributing to the development of distinct vascular diseases (VDs). However, functional investigations into GPCR Abs and their mechanistic roles in VD pathogenesis remain limited. In addition, structural data on GPCR-Ab interactions and the resulting effects on Ab-mediated signaling and protein expression are lacking. This limited knowledge represents a critical barrier to therapeutically targeting Ab-influenced processes and the translation of findings into clinical application. Our consortium have identified specific GPCR Abs as key modulators in diseases such as atherosclerotic vascular disease (ASVD) and pulmonary arterial hypertension (PAH). Furthermore, we have produced agonistic monoclonal Abs (mAbs) directed against the angiotensin receptor type-1 (AT1R), each with distinct phenotypic and functional properties. It allows us to conduct structure-function analyses and comparisons with polyclonal Abs from immunoglobulin (IgG) fractions of patients with VDs and healthy controls. In this proposal we aim to integrate functional studies of specific GPCR Abs and of Ab-induced pathways in ASVD and PAH, along with structural characterization of Ab–GPCR interactions. In particular, we will (i) identify optimal patient cohorts for IgG isolation for functional analyses using expression profiles of target cells and tissues involved in VDs, (ii) investigate downstream Ab-mediated signaling pathways contributing to VDs and test the ability of available GPCR blockers to inhibit them, (iii) characterize molecular interactions between Abs and GPCRs to identify potential receptor regions for therapeutic blockade of pathogenic Ab binding. To achieve these objectives, we have assembled an interdisciplinary team of experts in clinical medicine, GPCR immunology, biophysics and structural biology. We will utilize well-characterized VD patient cohorts with high GPCR Ab levels and employ a variety of cellular systems, including G protein activation assays, GPCR-transfected yeast, Ab internalization, and functional assays. We will perform transcriptomic and proteomic profiling in cells, tissues and organoids to assess Ab-induced responses. Functional data will be combined with structural data of GPCR-mAbs complexes determined by cryogenic electron microscopy. We will apply our established pipelines in receptor mutagenesis, structural biology, biophysics and computational modeling to define Ab binding motifs, affinities and sites for potential therapeutic Ab blockers. This integrative approach will close the gap between functional and structural insights into GPCR Ab biology and establish a novel framework for targeting Ab-driven mechanisms in vascular diese
DFG Programme
Research Units
