The biological consequences of cytoplasmic damage are largely unknown. The prevailing dogma considered the genotoxic effects of environmental carcinogens such as polycyclic aromatic hydrocarbons and radon alpha particles as being due mostly to direct damage to the nucleus. Using a precision charged particle microbeam and dual fluorochrome dyes to locate nucleus and cellular cytoplasm respectively, thereby avoiding inadvertent traversal of nuclei, the applicant has shown previously that cytoplasmic irradiation is, in fact, mutagenic at the CD59 locus of human-hamster hybrid (AL) cells while inflicting minimal cytotoxicity. Furthermore, preliminary evidence suggests that reactive oxygen species mediate this process. This raised the following questions: What types of oxyradicals are involved and what are their origins? Does this radical generating process involve mitochondrial damage? Do the mutations induced by targeted cytoplasmic irradiation occur in human bronchial epithelial cells (target tissues of environmental radon) as well? And finally, can cytoplasmic irradiation induce bystander mutagenic effect in mammalian cells in a manner similar to what the applicant has recently demonstrated with nuclear traversal of the AL cells. To address these issues, a series of 5 specific aims are proposed to address the 4 testable hypotheses. Mutations will be scored at the CD59 locus of the AL cells and at the HPRT locus in primary human bronchial epithelial cells. The proposed studies will help to address the mechanisms of how cytoplasmic irradiation results in a genetic event in the nucleus. Together with the bystander mutagenic effect, the study will address some of the fundamental issues regarding extranuclear target and how cytoplasmic damages are being processed in mammalian cells. ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Project (R01)
Project #
1R01ES012888-01
Application #
6756074
Study Section
Special Emphasis Panel (ZRG1-TPM (02))
Program Officer
Mcallister, Kimberly A
Project Start
2004-05-03
Project End
2009-03-31
Budget Start
2004-05-03
Budget End
2005-03-31
Support Year
1
Fiscal Year
2004
Total Cost
$374,208
Indirect Cost
Name
Columbia University (N.Y.)
Department
Radiation-Diagnostic/Oncology
Type
Schools of Medicine
DUNS #
621889815
City
New York
State
NY
Country
United States
Zip Code
10032
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