Susceptibility to radiation-induced normal tissue damage varies among individuals and some of this variation is assumed to have a genetic basis. However, the extent to which naturally occurring genetic polymorphisms influence the severity of normal tissue damage resulting from radiotherapy is unknown. This project is designed to quantify the genetic contribution to observed interindividual variations in radiation-induced normal tissue damage by applying emerging technologies in quantitative genetics in murine model systems. Murine models are suitable for this type of investigation because he strain variations in radiosensitivity result from naturally occurring genetic polymorphisms and there is abundance of radiobiological genetic mapping data available in this species. Preliminary studies revealed strain-specific differences in the levels of radiation-induced thymocyte apoptosis in C57BLJ6J and C3Hf/Kam mice. Genetic analysis of their F2 progeny has allowed the mapping of several of the genes responsible. A similar strain difference was observed in levels of jejunal crypt cell apoptosis, jejunal crypt survival, colon fibrosis and lung fibrosis following irradiation.
The specific aims of this project are to quantitate the genetic components of variation in the levels of radiation-induced apoptosis of thymocyte and jejunal crypt cells and jejunal crypt survival and to determine the inheritance pattern and map the major gene(s) involved in determining the variation in jejunal crypt apoptosis. Studies are planned to categorize radiation- induced apoptosis of thymocytes and jejunal crypt cells, jejunal crypt survival, colon fibrosis and lung fibrosis by their occurrence in C57BL6JXC2Hf/HeJ recombinant inbred mouse strains. In addition, strain differences in injury to clinically important late responding tissues will be characterized and methods to convert radiobiological effect data into quantitative traits that can be manipulated for genetic analyses will be evaluated.
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