Digital Public Defence: Stig Ree Krüger
MD Stig Krüger at Institute of Clinical Medicine will be defending the thesis Specific Notch signaling blockade in inflammation: Examples of in vivo applications for the degree of PhD (Philosophiae Doctor).
The public defence will be held as a video conference over Zoom.
The defence will follow regular procedure as far as possible, hence it will be open to the public and the audience can ask ex auditorio questions when invited to do so.
Due to copyright reasons, an electronic copy of the thesis must be ordered from the faculty. In order for the faculty to have time to process the order, it must be received by the faculty no later than 2 days prior to the public defence. Orders received later than 2 days before the defence will not be processed. Inquiries regarding the thesis after the public defence must be addressed to the candidate.
Digital Trial Lecture – time and place
- First opponent: Kennedy Trust Senior Clinical Research Fellow Adam Croft, Institute of Inflammation and Ageing, University of Birmingham, UK
- Second opponent: Senior Research Scientist Meritxell Nus, Cambridge Cardiovascular, Cambridge University, UK
- Third member and chair of the evaluation committee: Professor Tom Eirik Mollnes, Faculty of Medicine, University of Oslo
Chair of the Defence
Professor Emeritus Frode Vartdal, Faculty of Medicine, University of Oslo
Professor II Guttorm Haraldsen, Faculty of Medicine, University of Oslo
Inflammation depends on endothelial activation for the recruitment of leukocytes. Increasing our understanding of mechanisms involved might reveal novel therapeutic targets for anti-inflammatory treatment.
The aims of the thesis were first to assess the functions of endothelial-specific Notch signaling during inflammation. Through in vitro modulations of isolated human endothelial cells, the scientists revealed a Notch-dependent mechanism shaping the epigenetic landscape in favor of endothelial pro-inflammatory activation. These results were validated in vivo using endothelial-specific gene modifications of Notch in mice with contact hypersensitivity.
Building on this finding, mouse models of human disease were implemented to study the effects of antibodies blocking specific members of the Notch pathway. Antibody efficacy was compared using clinical, histopathological and molecular parameters in models of rheumatoid arthritis. Mice with arthritis had a significant reduction in disease progression when inhibition was targeting one of the four Notch receptors, and substantially reduced intestinal side effects compared to global Notch inhibition. The results suggest a specific Notch-receptor as novel target in treating patients with rheumatoid arthritis.
In a mouse model for choroidal neovascularization (CNV) - a leading cause of blindness in the Western world – specific inhibition of the Notch ligand Jagged1 reduced leukocyte infiltration, neovascularization and leakage from the neovasculature. Importantly, this treatment did not counteract anti-VEGF - today's gold standard in the treatment of human CNV.
In conclusion, this thesis increase our understanding of Notch in inflammation, reveals novel therapeutic targets within the Notch signaling pathway, and gives examples of how specificity could increase translational potential when targeting the Notch pathway.
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