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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA064193-02
Application #
2414329
Study Section
Radiation Study Section (RAD)
Project Start
1996-07-15
Project End
2000-04-30
Budget Start
1997-05-01
Budget End
1998-04-30
Support Year
2
Fiscal Year
1997
Total Cost
Indirect Cost
Name
University of Texas MD Anderson Cancer Center
Department
Radiation-Diagnostic/Oncology
Type
Other Domestic Higher Education
DUNS #
001910777
City
Houston
State
TX
Country
United States
Zip Code
77030
Pilling, Darrell; Roife, David; Wang, Min et al. (2007) Reduction of bleomycin-induced pulmonary fibrosis by serum amyloid P. J Immunol 179:4035-44
Cavanaugh, Dawn; Travis, Elizabeth L; Price, Roger E et al. (2006) Quantification of bleomycin-induced murine lung damage in vivo with micro-computed tomography. Acad Radiol 13:1505-12
Gu, Jing Jin; Santiago, Lalaine; Mitchell, Beverly S (2005) Synergy between imatinib and mycophenolic acid in inducing apoptosis in cell lines expressing Bcr-Abl. Blood 105:3270-7
Beasley, T Mark; Yang, Dongyan; Yi, Nengjun et al. (2004) Joint tests for quantitative trait loci in experimental crosses. Genet Sel Evol 36:601-19
Du, Min; Irani, Roxanna A; Stivers, David N et al. (2004) H2-Ea deficiency is a risk factor for bleomycin-induced lung fibrosis in mice. Cancer Res 64:6835-9
Cavanaugh, Dawn; Johnson, Evan; Price, Roger E et al. (2004) In vivo respiratory-gated micro-CT imaging in small-animal oncology models. Mol Imaging 3:55-62
Gu, Jing Jin; Gathy, Karen; Santiago, Lalaine et al. (2003) Induction of apoptosis in IL-3-dependent hematopoietic cell lines by guanine nucleotide depletion. Blood 101:4958-65
Haston, Christina K; Wang, Min; Dejournett, Robert E et al. (2002) Bleomycin hydrolase and a genetic locus within the MHC affect risk for pulmonary fibrosis in mice. Hum Mol Genet 11:1855-63
Haston, Christina K; Zhou, Xinhui; Gumbiner-Russo, Laura et al. (2002) Universal and radiation-specific loci influence murine susceptibility to radiation-induced pulmonary fibrosis. Cancer Res 62:3782-8
Travis, E L (2001) Organizational response of normal tissues to irradiation. Semin Radiat Oncol 11:184-96

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