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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: Head of Department Anne-Karine Bouzier-Sore, Université de Bourdeaux, France
- Second opponent: Associate professor Samuel Geiseler, UiT - The Arctic University of Norway,
- Third member and chair of the evaluation committee: Professor Mahmood Amiry-Moghaddam, University of Oslo
Chair of the Defence
Professor Anne Gjøen Simonsen, University of Oslo
Principal Supervisor
Associate Professor Johanne Egge Rinholm, University of Oslo
Summary
Neonatal Hypoxia ischemia (HI) is one of the leading causes of death and disability in the developed world. Hypothermia is the main treatment, but many still experience long-term neurological deficits, underlining the need for improved therapy. Lactate has shown neuroprotective effects following HI in mice, and this thesis investigates the role of the lactate receptor, Hydroxycarboxylic Acid Receptor 1 (HCAR1), in HI. Given the limitations of translating mouse model findings to humans, we also aimed to develop a human tissue model for HI.
To investigate the role of HCAR1 after HI, we used a mouse model for neonatal HI where we included mice that lack the HCAR1 gene (HCAR1 knockout (KO) mice). While HCAR1 KO and wildtype (WT) mice had a similar acute brain damage, HCAR1 KO mice had significantly less regeneration of brain tissue after the injury. This was accompanied by reduced gene regulation of important processes in tissue regeneration such as neurogenesis and innate immunity in the HCAR1 KO mice. Another key aspect of the repair process is cell migration into the damaged region. Using neural progenitor cells from mice, we found that cells from HCAR1 KO mice had reduced migration compared to WT cells. Thus, HCAR1 is a positive regulator of migration.
The lack of translatability between mouse models and human clinical trials is a challenge for drug development. Therefore, this dissertation also focused on developing a HI model based on human cells. Here we generated cerebral organoids from human stem cells. The organoids were enriched with oligodendrocytes, the myelin producing cells, which are more numerous in human than mural brains. We showed that oligodendrocytes and neural progenitor cells in the organoids displayed similar responses to ischemia and drug interventions as those found in mice. This human model for ischemic brain injury could help assess treatments that showed promise in mice before advancing to clinical trials.
Additional information
Contact the research support staff.