The main objective of the present project is to explore the metabolism of tryptophan through the kynurenine pathway in abdominal aortic aneurysms (AAA) in order to identify new therapeutic and diagnostic targets for the disease. In order to reach our goals, the following interconnected aims are proposed
1a) Characterize the kynurenine pathway in human AAA tissue samples
1b) Evaluate the levels of kynurenines in plasma of AAA patients and controls
2) Evaluate the potential of the pharmacological inhibition of the kynurenine pathway enzymes to prevent experimental AAA.
Targeting the kynurenine pathway of tryptophan degradation to combat abdominal aortic aneurysm
Generally asymptomatic, rupture of abdominal aortic aneurysms (AAA) leads to lethal bleeding and death in 65-85% of cases. While treatment relies almost exclusively on surgical intervention, proven drugs to prevent AAA remain absent. Strong evidence indicates that targeting the inflammatory process driving AAA pathogenesis could be a suitable approach against this disease. Our group has shown that modulating the kynurenine pathway (KP) of tryptophan degradation halts vascular inflammation and atherosclerosis. Whether targeting of the KP can protect against AAA remains unclear.
This project will characterize in depth the KP in AAA, and explore new potential therapeutic and diagnostic targets against it
In this context, we will:
This work carries the potential to reveal whether the KP enzymes and metabolites can regulate major inflammatory components in the vascular wall, including activation of the NFκB and the inflammasome on macrophages, antigen presentation and T cell expansion, and the deleterious dedifferentiation of vascular SMCs.
Jes Sanddal Lindholt, University of Southern Denmark, Department of Clinical Research
Lars Melholt Rasmussen, Department of Clinical Research, University of Southern Denmark & Head of Research at Dept. of Clinical Biochemistry and Pharmacology, Odense University Hospital
Daniel F. J. Ketelhuth, Professsor, University of Southern Denmark