Due to copyright issues, an electronic copy of the thesis must be ordered from the faculty. For the faculty to have time to process the order, the order must be received by the faculty at the latest 2 days before the public defence. Orders received later than 2 days before the defence will not be processed. After the public defence, please address any inquiries regarding the thesis to the candidate.
Trial Lecture – time and place
See Trial Lecture.
Adjudication committee
- First opponent: Professor Sander Tas, University of Amsterdam, The Netherlands
- Second opponent: Senior Consultant Øystein Sandanger, Oslo University Hospital
- Third member and chair of the evaluation committee: Professor Marit Inngjerdingen, University of Oslo
Chair of the Defence
Professor Emeritus Frode Vartdal, University of Oslo
Principal Supervisor
Professor Guttorm Haraldsen, University of Oslo
Summary
Difficult-to-treat diseases are a focus of many investigators, as reaching the treat-to-target goal is not trivial. Modern therapeutic approaches improved effectiveness of pharmacological treatment in several disorders, yet significant fractions of patients with chronic inflammation, including rheumatoid arthritis (RA) patients respond insufficiently to therapy.
The thesis describes elements of the Notch pathway involved in RA and how possible therapeutic manipulations of the pathway can be exploited to attenuate the disease progression studied on animal experimental models and human material. The project involved expertise in rheumatology, single cell genomics and experimental pathology.
We have discovered that selective Notch2 inhibition strongly attenuates experimental arthritis. We have identified Notch2-expressing synovial fibroblasts, macrophages and osteoclasts in affected joints. Transcriptional profiles of these cell populations were modulated, and changes included transcripts of inflammation, osteogenesis, angiogenesis, cell survival, suggesting that these cell types are responsible for the ongoing inflammation and bone destruction in arthritic mice. Notch2 was also present in RA-patient synovial cells. The efficacy of Notch2 inhibition confirmed anti-inflammatory effect in human synovial cell in vitro cultures.
This preclinical study shows that Notch2 inhibition is an attractive therapeutic strategy for difficult-to-treat diseases and may be a promising alternative treatment for arthritis and many other chronic inflammatory diseases.
Additional information
Contact the research support staff.