Forsøksdyr: DNA repair, immune system and coagulation in atherosclerosis and related metabolic disorders


Godkjenningsdato 18.05.2020

Godkjenningsperiode 01.06.2020-31.05.2024

1. Hallmarks of cardiovascular disorders belong to both inflammatory- and metabolic dysfunction. Damage to the arterial wall leading to atherosclerosis activates the immune system. Coagulation factors initiates the formation of a thrombus, and immune cells mediates the inflammatory response and tissue repair. In addition, both genetic and epigenetic dispositions affect the risk of disease development and outcome of disease progression. Mice deficient in DNA-repair enzymes have altered inflammatory and metabolic pathways, reflecting their role in epigenetic regulation. This project aims to characterize the importance of a fully functional DNA repair system, immune system and/or coagulation cascade in the development and progression of atherosclerosis and underlying metabolic disorders. In addition, we will clarify the role of the microbiota and the effect of promising therapeutic agents.

2. This project include surgical procedures performed under deep anesthesia (moderate stress) in addition to some mildly stressful procedures including pinpricks for blood sampling and non-invasive imaging under anesthesia. Proper analgesic treatment will be provided after surgery, and procedures are scheduled to allow full recovery and no cumulative effects of multiple/repeated procedures. We evaluate the stress level to "moderate".

3. This project will characterize the importance of a fully functional DNA repair system, immune system and/or coagulation cascade and microbiome in the development and progression of atherosclerosis and underlying metabolic disorders. Based on this knowledge we will also conduct intervention studies, assessing the therapeutic potential of promising compounds.

4. Mus musculus, this project consists of well-defined work packages. In each experimental group, we will use 10 mice of each relevant genotype. This number allows us to study both genders and will also give us flexibility terminate suffering animals without compromising the statistical validity. In total, 5057 mice (31 different genotypes).

5. The interplay between individual cells, tissues and organs, and their obvious impact on the whole organism and its phenotype cannot be properly studied outside a living animal. Considerable individual variations are to be expected for cardio-metabolic studies in mice. The number of mice chosen for this project will allow us freedom to terminate animals showing discomfort, sickness or injuries without compromising the statistical validity of our study, and allow us to include both genders. This project will utilize the mice generated from our breeding project (FOTS approval #22322) which will minimize the generation of research animals, and our restrictive breeding plan directs us to only produce the animals needed for our research, and to reduce the number of individuals in any given experiment to a minimum The mice will be checked on a daily basis by KPM staff, and monitored on a weekly basis by project researchers. Anesthesia and analgesia will be properly administered.