Development and characterisation of mouse models for the determination of the genetic components of radiation sensitivity

Radiation sensitivity is a serious problem in cancer therapy which leads to an early termination or interruption of therapy in about 15% of the cases due to uncontrollable side effects. With the exception of rare genetic synd romes such as AT (Ataxia Telangiectasia) or NBS (Nijmegen breakage syndrome ), the background for the inheritance of genetic susceptibility to radiatio n is unknown. Recently, a large scale genetic screen of mouse mutants has been establishe d within the German Human Project as a collaboration between the Institute of Mammalian Genetics, GSF Research Center and the Gene Center of the Ludwi g Maximillian University in Munich. The goal of this ENU (ethyl-nitroso-ure a) mutagenesis screen is the production of mutant mice by chemical mutagene sis which are characterized by specific phenotypic abnormalities and can se rve as animal models for human diseases and genetic susceptibility. All mic e are phenotypically screened for about 150 biochemical, immunological, and morphological parameters, respectively. The genetic screen is expected to generate between 1000 and 2000 new mouse mutants within the next 5 to 10 ye ars. In order to utilise the resources of a genetic screen of this magnitude for screening for radiation sensitivity, it is necessary to establish an in vi tro assay system which is amenable to automatization. Hence, we are using t he corner assay to detect mice mutants which display a genetic susceptibili ty to ionising radiation. Currently, we have established comet assay analys is parameters able to detect radiation sensitive mouse mutants and to contr ol the variance within the mouse population in the ENU screen. The principl e goal of our effort is to isolate genes which are responsible for DNA repa ir and radiation sensitivity in mouse and man.