Biological mechanisms of the ionizing radiation response in lens epithelial cells

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The long-term goals of this research program are to investigate the mechanisms behind the biological response to low dose radiation. Ionizing radiation can result in an increase in oxidative stress, genetic mutations and carcinogenesis, and this has been well documented following high dose acute exposures. However, there is still debate regarding the biological implications of radiation exposure in the low dose region. There is growing evidence that living systems respond differently to low dose radiation and many current models of risk support a threshold or hormetic relationship. My past work has explored several aspects of low dose and low dose rate radiation, and these topics will continue to be investigated in the research program in radiobiology that I am establishing. The short-term goals of this specific proposal are to investigate the biological response to ionizing radiation exposure in the lens of the eye. The mammalian lens is believed to be one of the most radiosensitive tissues. However, there has recently been debate regarding the role that dose rate plays in lens damage and whether there is a threshold dose for radiogenic effects. The proposed research will investigate these fundamental questions by studying the mechanism of x-radiation exposure in cultured lens epithelial cells (LEC). In the first aim, the dose response for oxidative stress and genomic damage will be compared across several acute and protracted dose rates. Next, functional changes and alterations in cell proliferation resulting from this radiation-induced genomic damage will be investigated. Finally, we will identify transcript and protein changes involved in the low dose radiation response. This initial proposal will focus on cellular and molecular changes in cultured LEC. Follow up studies will incorporate animal models to validate the observed radiogenic effects on the lens in-vivo. The results of this ongoing research program in low dose radiobiology will advance our understanding of the cellular response to genotoxic damage and oxidative stress induced by ionizing radiation. The data generated from this specific proposal will help to fill in critical gaps in our understanding of the mechanism of radiation exposure to the lens of the eye. As the lens is known to be radiosensitive, it can serve as a bioindicator for radiation damage to other tissues. In addition, this research will help to answer fundamental questions regarding the role of dose rate and the presence of radiation thresholds. Ionizing radiation is something that all biological systems are exposed to on a daily basis from natural background sources and organisms have adapted to living with this low level stress. Elucidating the effects of radiation is essential with its growing use in medical diagnostics, therapeutic procedures and occupational practices.