Breeding of DNA glycosylase mutant mice
Oxidative DNA damage arises as a consequence of normal metabolism but also by various environmental stimuli, and is believed to play an important role in the development of cancer and normal aging and neurodegeneration. Oxidative DNA damage is primarily repaired by the base excision repair (BER) pathway. DNA glycosylases initiate BER by recognizing and excising the damaged base. To date, six mammalian DNA glycosylases that remove a variety of oxidative base lesions have been identified.
So far, no severe phenotypes have been observed in the KO mice. Only the OGG/Muty DKO has shown an increased cancer susceptibility, so we will sacrifice these at the age of 6 months, before developing cancer. Notably, our group demonstrated that DNA glycosylases play an important role in the brain by regulating neuronal function. To further elucidate the role of DNA glycosylases in brain function, we would like to use Neil1 KO, Neil2 KO, Neil3 KO, Ogg1 KO, Muty KO, OGG/Muty DO KO, Neil1/Neil2 DO KO, and C57/bl6N as a control for all mutant mice. Moreover, to better decipher the underlying mechanism of the glycosylases action we would like to use mice that harbour a catalytic inactive variant of the respective DNA glycosylases.
To date it is not possible to model those complex diseases in vitro without the use of appropriate animal models. The application is for breeding and behavioral testing, thus no adverse effects are expected. All our experiments are well planned to avoid an excess use of animals. Animals, which are used for breeding, will be included in experiments for later time points to reduce the total amount of mice needed for the analyses.
We apply for 2400 animals over 4 years. Of those, 1350 animals will go through cognitive testing. Mice will also be used in other research projects, so we expect the number of mice used for breeding to be less than 2400.
So far, no severe phenotypes have been observed in the KO mice. Only the OGG/Muty DKO has shown an increased cancer susceptibility, so we will sacrifice these at the age of 6 months, before developing cancer. Notably, our group demonstrated that DNA glycosylases play an important role in the brain by regulating neuronal function. To further elucidate the role of DNA glycosylases in brain function, we would like to use Neil1 KO, Neil2 KO, Neil3 KO, Ogg1 KO, Muty KO, OGG/Muty DO KO, Neil1/Neil2 DO KO, and C57/bl6N as a control for all mutant mice. Moreover, to better decipher the underlying mechanism of the glycosylases action we would like to use mice that harbour a catalytic inactive variant of the respective DNA glycosylases.
To date it is not possible to model those complex diseases in vitro without the use of appropriate animal models. The application is for breeding and behavioral testing, thus no adverse effects are expected. All our experiments are well planned to avoid an excess use of animals. Animals, which are used for breeding, will be included in experiments for later time points to reduce the total amount of mice needed for the analyses.
We apply for 2400 animals over 4 years. Of those, 1350 animals will go through cognitive testing. Mice will also be used in other research projects, so we expect the number of mice used for breeding to be less than 2400.