) The goal of this application is to analyze the molecular, genetic, cytogenetic and cellular mechanisms that initiate and perpetuate genomic instability after cellular exposure to radiations commonly encountered in space. This goal will be addressed by means of five specific aims.
Specific aim 1 will test the hypothesis that genomic instability, as measured by delayed chromosomal instability, can be induced by high-energy protons, high-Z and high-energy (HZE) iron ions, and high LET alpha particles in both log-phase and confluence arrested cells.
Specific aim 2 will test the hypothesis that the critical cellular target for high LET-induced genomic instability is located in both the nuclear and extranuclear cellular compartments. This will be achieved by selectively targeting the cell nucleus and/or the plasma membrane and cytoplasm to more than 1 alpha particle, or to the decay of 125iodine incorporated into the DNA as 125IUdR or bound to the plasma membrane as 125I-conjugated concanavalin A.
Specific aim 3 will test the hypothesis that cells showing one point of genomic instability, e.g., chromosomal instability, demonstrate a """"""""mutator"""""""" phenotype and display other endpoints of instability, specifically, increased mutation at the HPRT and APRT loci, gene amplification at the DHFR and CAD loci, increased SCE levels, and delayed reproductive cell death.
Specific aim 4 will test the hypothesis that high LET radiation-induced genomic instability is increased in isogenic repair-deficient cell lines as a function of known mutations in DNA doublestrand-break repair.
Specific aim 5 will test the hypothesis that there is a molecular basis for induced genomic instability that can be observed cytogenetically. The applicant will monitor instability of the (TTAGGG)n interstitial telomere-like repeat sequence and use comparative genomic hybridization to identify chromosomal regions that are consistently different between unstable and stable clones.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA073924-03
Application #
2895896
Study Section
Special Emphasis Panel (ZCA1-CRB-X (J1))
Program Officer
Pelroy, Richard
Project Start
1997-09-30
Project End
1999-07-31
Budget Start
1999-04-01
Budget End
1999-07-31
Support Year
3
Fiscal Year
1999
Total Cost
Indirect Cost
Name
University of California San Francisco
Department
Radiation-Diagnostic/Oncology
Type
Schools of Medicine
DUNS #
073133571
City
San Francisco
State
CA
Country
United States
Zip Code
94143
Durant, Stephen T; Paffett, Kimberly S; Shrivastav, Meena et al. (2006) UV radiation induces delayed hyperrecombination associated with hypermutation in human cells. Mol Cell Biol 26:6047-55
Kim, Grace J; Chandrasekaran, Krish; Morgan, William F (2006) Mitochondrial dysfunction, persistently elevated levels of reactive oxygen species and radiation-induced genomic instability: a review. Mutagenesis 21:361-7
Snyder, Andrew R; Morgan, William F (2005) Differential induction and activation of NF-kappaB transcription complexes in radiation-induced chromosomally unstable cell lines. Environ Mol Mutagen 45:177-87
Nagar, Shruti; Smith, Leslie E; Morgan, William F (2005) Variation in apoptosis profiles in radiation-induced genomically unstable cell lines. Radiat Res 163:324-31
Nagar, Shruti; Morgan, William F (2005) The death-inducing effect and genomic instability. Radiat Res 163:316-23
Snyder, Andrew R; Morgan, William F (2004) Gene expression profiling after irradiation: clues to understanding acute and persistent responses? Cancer Metastasis Rev 23:259-68
Huang, Lei; Grim, Suzanne; Smith, Leslie E et al. (2004) Ionizing radiation induces delayed hyperrecombination in Mammalian cells. Mol Cell Biol 24:5060-8
Snyder, Andrew R; Morgan, William F (2004) Radiation-induced chromosomal instability and gene expression profiling: searching for clues to initiation and perpetuation. Mutat Res 568:89-96
Sowa Resat, Marianne B; Morgan, William F (2004) Radiation-induced genomic instability: a role for secreted soluble factors in communicating the radiation response to non-irradiated cells. J Cell Biochem 92:1013-9
Huang, Lei; Snyder, Andrew R; Morgan, William F (2003) Radiation-induced genomic instability and its implications for radiation carcinogenesis. Oncogene 22:5848-54

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