P6: Rolle von PAR-Autoantikörpern in der Aggravation und Prognose vaskulärer Erkrankungen

• Antragstellerinnen / Antragsteller: Professor Dr. Matthias Endres; Guido Moll, Ph.D.; Professorin Dr. Gabriela Riemekasten
• Fachliche Zuordnung: Rheumatologie ; Experimentelle Modelle zum Verständnis von Erkrankungen des Nervensystems ; Kardiologie, Angiologie ; Klinische Immunologie und Allergologie ; Pneumologie,Thoraxchirurgie
• Förderung: Förderung seit 2026
• Projektkennung: Deutsche Forschungsgemeinschaft (DFG) - Projektnummer 552470287

Arteriosclerotic vascular disease (ASVD), ischaemic stroke (IS), and pulmonary arterial hypertension (PAH) are severe vascular disorders and common co-morbidities in autoimmune diseases (ADs). Thrombotic processes and vascular remodelling, mediated by the activation of Protease-Activated Receptors 1 and 2 (PAR1 and PAR2), respectively, are key events in the pathogenesis and prognosis of these conditions. Recent evidence has identified autoantibodies (Abs) against PAR1 and PAR2 as novel modulators of these receptors. Our epidemiological studies across multiple cohorts have demonstrated elevated levels of PAR1 Abs in patients with thromboembolic events and vascular diseases, and increased levels of PAR2 Abs in those with ischaemic stroke. Notably, high levels of both PAR1 and PAR2 Abs correlate with worse clinical outcomes. Functional studies indicate that PAR1 Abs promote thromboembolic and inflammatory processes, while PAR2 Abs appear to play a key role in vascular remodelling. These findings suggest that PAR1 and PAR2 Abs may act as critical modulators of receptor function, influencing both the presence and progression of vascular diseases. This study aims to investigate the relationship between PAR1 and PAR2 Ab levels and disease outcomes in detail. Specifically, we will: i) correlate PAR1 and PAR2 Ab levels with clinical outcomes in well-characterized patient cohorts with PAH, ASVD, and IS, ii) investigate the interactions of these Abs with endothelial cells, immune cells, and platelets in vitro; and iii) assess their in vivo impact using established preclinical models of PAH, ASVD, and IS. To uncover disease-overarching mechanisms, the influence of individual Ab specificities alone or in the concert of other Abs, we have assembled a team of rheumatologists, a neurologist, and an immunologist. In this study, we will integrate Ab-based mouse models with a comprehensive array of cellular assays to elucidate Ab-receptor interactions and their effects at the cellular and tissue levels. Advanced technologies such as single-cell RNA sequencing and imaging mass cytometry will be employed in our preclinical models to analyze the impact of these Abs at both the transcriptomic and proteomic levels. These molecular and cellular data will be integrated with disease-specific imaging and diagnostic tools, including 3D computational analysis of atherosclerotic lesions, right heart catheterization, and cerebral magnetic resonance imaging. Our interdisciplinary and translational approach is designed to yield essential insights into the pathogenic role of PAR1 and PAR2 Abs in vascular diseases. By identifying a novel, overarching mechanism contributing to disease progression and outcomes, this study aims to pave the way for new therapeutic strategies targeting PAR autoantibodies in inflammatory vascular pathologies.

• DFG-Verfahren: Forschungsgruppen
• Teilprojekt zu: FOR 5930: Autoantikörper gegen G Protein-gekoppelte Rezeptoren als Treiber vaskulärer Erkrankungen (AbsInVasc)