Developmental mechanisms in KRAS-driven arteriovenous malformations

• Applicant: Privatdozent Dr. Friedrich Kapp
• Subject Area: Pediatric and Adolescent Medicine
• Term: since 2026
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 571386042

Arteriovenous malformations (AVMs) are rare vascular anomalies characterized by a direct connection between arteries and veins. The absence of the capillary bed results in a reduced resistance between these two vascular systems, leading to vessel dilation and weakening of their walls. AVMs often grow during childhood and can cause severe complications such as tissue necrosis, life-threatening bleeding, and heart failure. Current treatment options are limited to embolization and surgical intervention. However, even after these procedures, AVMs recur in approximately 80% of cases. No approved medical therapy is currently available. The development of new therapies is hindered by insufficient knowledge about the mechanisms underlying AVM formation and maintenance. In this project, we aim to deepen our understanding of the processes involved in AVM development by investigating the molecular effects of KRAS G12D - the mutation most frequently found in our cohort of patients with AVMs. KRAS G12D leads to hyperactivation of the RAS signaling pathway. The goal of this project is to gain a better understanding of the pathophysiology of AVM development using a zebrafish model and molecular characterization of patient samples, thereby identifying new therapeutic targets. Simultaneously, we will gain new insights into the role of RAS signaling in normal vascular development. To achieve this, we will first characterize the phenotype and penetrance of KRAS G12D-driven vascular malformations in the zebrafish model and compare it with mutations found in other vascular malformations. Subsequently, we will identify critical time points for AVM development by using time-lapse confocal microscopy to analyze abnormal behavior of multipotent precursors from the lateral plate mesoderm, aberrant development of the vascular system, and potentially altered endothelial cell identity. In the next step, we will investigate which signaling pathways are dysregulated in the responsible cells at critical time points of AVM development due to the KRAS G12D mutation. For this purpose, we will examine gene expression and chromatin accessibility in KRAS G12D-expressing zebrafish endothelial cells using RNA- and ATAC-sequencing. We will assess the identified alterations as potential therapeutic targets using drug treatments in the zebrafish model. Finally, we will validate the transferability of results to humans through a cross-species comparison of zebrafish sequencing results with single-cell RNA and ATAC sequencing results from patient samples.

• DFG Programme: Research Grants
• International Connection: USA
• Cooperation Partner: Professor Dr. Leonard Zon