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The biological outcomes after radiation exposure are complex, and are influenced by genetic, epigenetic and other somatic factors. The overall project goal is to determine if DNA damage produced in critical stem cell populations after low-dose low-LET radiation exposure is cleared by DNA repair processes and/or apoptosis, or persists and leads to genomic instability.
The hypotheses being tested are the following:
1) Does DNA damage persists in stem cell populations after low-dose radiation exposures, leading to genomic instability, because low-levels of radiation-induced DNA damage evade ATM-dependent cellular damage recognition processes?
2) Does immunological stress prior to radiation exposure enhances DNA damage processing in stem cell populations and is such an enhancement functionally radioprotective?
DNA damage, apoptosis, and DNA methylation will be assayed in the hemopoietic stem cells at short- and long-term intervals after exposure to a range of single radiation doses. Stem cells will be identified and isolated from bone marrow using a novel flow cytometry cell sorting technique known as 'side population' analysis. This approach will permit radiation risks to be defined for this critical stem cell population despite its low abundance in the bone marrow. The incidence and repair of DNA double strand breaks (DSB) will be assessed by γH2AX foci, apoptosis by caspase-3 activation and DNA methylation evaluated by a cytosine extension assay. Data from the three endpoints will be compared to determine if DNA damage is cleared or if it persists, leading to genomic instability. Secondly, we shall determine if immunological stress prior to radiation exposure changes the response of stem cells to low-dose irradiation injury.
These experiments will define the radiation response of stem cells to low-dose radiation damage after a period of in situ damage processing. The results will aid the definition of low-dose radiation risk in a dose range where current epidemiological data are deficient, and can be used to assist in the definition of damage induced in patients following radiation therapy for cancer. Moreover, studying how immunological stress modifies low-dose radiation response provides a degree of relevance in determining how health status may impact the carcinogenic risk associated with human radiation exposures.