Project Details
Projekt
P7: Dissecting mechanisms and modifiers of AT1R-induced obliterative vasculopathy
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
Pulmonary arterial hypertension (PAH) is frequently associated with autoimmune and connective tissue diseases, particularly systemic sclerosis (SSc). In SSc patients, PAH arises from immune-mediated endothelial dysfunction, chronic inflammation, and vascular remodelling, leading to structural narrowing or obliteration of small pulmonary arteries. Angiotensin II type 1 receptor autoantibodies (AT1R Abs) are elevated in SSc patients and are associated with an increased risk of severe manifestations, including SSc-associated PAH (SSc-PAH). Recently, we have established a novel experimental model for SSc-PAH by immunizing IL-13 transgenic mice with human AT1R, revealing the relevance of AT1R Abs and IL-13 signalling in disease pathogenesis. Supporting this, our in vitro studies showed that IL-13 promotes hyperproliferation of human pulmonary arterial smooth muscle cells (PASMCs). A hypoxia-induced mouse model of pulmonary hypertension demonstrated higher IL-13 expression. Collectively, these data support the concept that the AT1R–AT1R Ab–IL-13 axis contributes significantly to the pathophysiology of PAH and may serve as a promising therapeutic target.In this project, we aim to elucidate the molecular mechanisms of AT1R Abs and IL-13 in the pathogenesis of SSc-PAH, with the overarching goal to identify novel therapeutic targets. Specifically, we will: i) investigate how AT1R Abs mediate the activation of endothelial cells and how AT1R+ immune cells expressing IL-13 contribute to the development PAH, ii) assess the role of endothelial AT1R overexpression and of hypoxia as co-pathogenic factors in the development of PAH, iii) identify novel potential therapeutic candidates for SSc-PAH through a drug-repurposing strategy, and iv) establish a microfluidic Organoplate-based model for PAH to determine therapeutic efficacy of blocking monoclonal antibodies against human IL-13 receptors.To achieve this, we will use two established mouse models of PAH to investigate the roles of AT1R, AT1R Abs, and hypoxia in the development of experimental PAH. Furthermore, we will employ adeno-associated virus (AAV)-mediated gene delivery to overexpress AT1R both in vitro and in vivo, allowing us to assess its role in endothelial activation and disease progression. An in vitro model of PAH will enable to study IL-13–mediated signalling pathways and their contribution to vascular remodelling. For further translation, we will implement a drug-repurposing strategy to identify existing compounds with potential therapeutic benefit for PAH, focusing on agents that modulate the IL-13 signalling. Additionally, a microfluidic Organoplate-based human PAH model will be developed to mimic IL-13-driven vascular pathology and to evaluate the efficacy of monoclonal antibodies targeting IL-13 receptor signalling pathways. Taken together, this subproject will provide new insights into the AT1R–IL-13 axis in PAH and help to identify effective therapeutic strategies.
DFG Programme
Research Units
