A basic paradigm in radiobiology is that following cellular exposure to ionizing radiation it is the deposition of energy in the cell nucleus that is responsible for its deleterious biological effects, and that DNA is the principal target for radiation damage. Two rapidly expanding fields of research, radiation-induced genomic instability and bystander effects (BSEs) have caused us to reevaluate this central dogma. In this application we will investigate the role of BSEs, i.e., those effects occurring in cells that were not irradiated, but were bystanders at the time of irradiation, in contributing to the deleterious effects of radiation exposure. We propose that some bystander effect factor (BSEF) is stimulated by cellular irradiation and secreted into the culture medium. We hypothesize that this BSEF is a protein to protein complex. The BSEF could itself be responsible for the observed BSEs in non-irradiated cells and/or could generate reactive oxygen species (ROS) and act in conjunction with these ROS to elicit BSEs. In turn these ROS could stimulate BSEF creating cycles of BSEF/ROS/BSEF/ROS, thus perpetuating a source of damage over time to account for the observed detrimental effects of X-irradiation. These hypotheses will be best addressed in 3 specific aims:
Specific aim 1 will test the hypothesis that the SBEF can mimic the deleterious effects of X-ray exposure in non-irradiated cells.
Specific aim 2 will test the hypothesis that our unique collection of chromosomally unstable cloned can produce """"""""instability"""""""" factor(s) that can induce cytogenetic damage and genomic instability in non-irradiated cells.
Specific aim 3 is to isolate, purify, and identify the factor(s) responsible for the BSE, and those """"""""instability"""""""" factors produced by unstable cells. We are uniquely qualified to do this. We have in hand the assays for potential BSEs, radiation-induced genomic instability, and a collection of well-characterized chromosomally unstable clones of cells. We have experience in isolating, purifying, and identifying potential BSEF(s) and have the methodology to test candidates. Identifying the BSEF would enhance our understanding of how radiation exerts its deleterious effects and could directly impact risk estimation for radiation exposure.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA083872-02
Application #
6497943
Study Section
Radiation Study Section (RAD)
Program Officer
Pelroy, Richard
Project Start
2001-02-15
Project End
2005-01-31
Budget Start
2002-02-01
Budget End
2003-01-31
Support Year
2
Fiscal Year
2002
Total Cost
$248,096
Indirect Cost
Name
University of Maryland Baltimore
Department
Radiation-Diagnostic/Oncology
Type
Schools of Medicine
DUNS #
003255213
City
Baltimore
State
MD
Country
United States
Zip Code
21201
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
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
Huang, Lei; Grim, Suzanne; Smith, Leslie E et al. (2004) Ionizing radiation induces delayed hyperrecombination in Mammalian cells. Mol Cell Biol 24:5060-8
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
Morgan, William F (2003) Non-targeted and delayed effects of exposure to ionizing radiation: II. Radiation-induced genomic instability and bystander effects in vivo, clastogenic factors and transgenerational effects. Radiat Res 159:581-96
Morgan, William F (2003) Is there a common mechanism underlying genomic instability, bystander effects and other nontargeted effects of exposure to ionizing radiation? Oncogene 22:7094-9
Morgan, William F (2003) Non-targeted and delayed effects of exposure to ionizing radiation: I. Radiation-induced genomic instability and bystander effects in vitro. Radiat Res 159:567-80
Nagar, Shruti; Smith, Leslie E; Morgan, William F (2003) Mechanisms of cell death associated with death-inducing factors from genomically unstable cell lines. Mutagenesis 18:549-60

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