The goal of this project is to provide a better understanding of the genetic basis of radiation-induced fibrosis in normal tissues so as to enable the rational development of predictive assays for this late sequelae of radiation therapy. The rationale for these studies is based on observations in humans and studies in experimental animals which suggest that sensitivity to radiation-induced tissue fibrosis is genetically regulated, although none of the genes involved in individual variation have been identified. Nonetheless, assays are being developed to prospectively identify susceptible individuals in the clinic before treatment commences. The proposed work will focus on determining the pattern of inheritance of radiation-induced lung fibrosis in the F2 progeny of an intercross of two mouse strains shown to differ markedly in their susceptibility to radiation-induced fibrosis, and subsequently mapping the locus (loci) that account for these differences. The approach will be to use the C57B1/6 mouse, a highly fibrogenic strain, and the C3H/HeJ mouse, a weakly fibrogenic strain and to breed these mice to obtain F1 and F2 progeny. To determine the inheritance pattern of fibrosis after irradiation, F2s will be exposed to a single dose of radiation which induces a significant difference in lung fibrosis in the parental strains. Lung fibrosis after irradiation will be quantitated in the whole lung by determining the area of a histological section of lung displaying the characteristic fibrotic phenotype. Fibrosis will be quantitated using a computerized image analysis system attached to a microscope. For gene mapping, DNA from 432 irradiated F2 mice will be used to type for 150 short sequence repeats (SSR) that are polymorphic between C57B1/6 and C3H/HeJ mice. The extent of fibrosis in the F2s will be correlated with their SSR genotype. The inheritance pattern of bleomycin-induced lung fibrosis had been characterized. The bleomycin studies to be performed will constitute mapping the loci that control bleomycin-induced lung fibrosis in 432 F2 mice. The data obtained from these studies have potential importance to clinical radiotherapy as they should provide a rational basis for the development of predictive assays for fibrosis in normal tissue, that will enable the radiotherapist to prospectively identify both sensitive and resistant individuals, and thus avoid overdosing radiosensitive individuals while not compromising on the dose to """"""""normal"""""""" individuals. The ultimate outcome would be more cures.
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