Abstract

This revised application is a competing renewal of a proposal to investigate radiation-induced genomic instability. The goal of this application is to consolidate the """"""""instability program"""""""" and focus on the molecular mechanisms and biological consequences of radiation-induced instability. The proposed studies are an expansion of current research from the PI's laboratory and will build upon observations made during the previous funding period. We propose to continue to validate a plasmid based recombination assay as a rapid and reliable indicator of delayed instability in cells post irradiation. Furthermore, we will utilize the extensive collection of chromosomally unstable clones of cells we have generated during the previous funding period to investigate the role of instability in radioresistance and determine differences in gene expression that may be responsible for the observed instability. To accomplish these goals there are three specific aims:
Specific aim 1 will test the hypothesis that a recombination assay based on expression of green fluorescence protein can be used to rapidly and efficiently identify unstable clones as a function of time after irradiation. We will characterize this plasmid based assay system in relationship to our well defined chromosomal assay and use it to determine the effects of fractionated radiation treatment, DNA repair inhibitors, and modifying the post irradiation on induced instability.
Specific aim 2 will expand upon our observation that genomic instability contributes to cellular radioresistance and we will investigate the hypothesis that this is due to differential gene expression.
Specific aim 3 will test the hypothesis that radiation-induced genomic instability has a molecular/genetic basis reflecting differential gene expression, and that differential display strategies and/or RNA hybridization strategies using microarray technology can be used to identify the gene(s) involved in initiating and/or perpetuating the unstable phenotype.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA073924-08
Application #
6621325
Study Section
Radiation Study Section (RAD)
Program Officer
Pelroy, Richard
Project Start
1997-09-30
Project End
2006-01-31
Budget Start
2003-02-01
Budget End
2004-01-31
Support Year
8
Fiscal Year
2003
Total Cost
$297,371
Indirect Cost

  Institution

Name
University of Maryland Baltimore
Department
Radiation-Diagnostic/Oncology
Type
Schools of Medicine
DUNS #
188435911
City
Baltimore
State
MD
Country
United States
Zip Code
21201

  Publications

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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