| DOI: | 10.2172/1009811
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| 报告号: | DOE-ER64055-1
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| 报告题名: | Cellular response to low dose radiation: Role of phosphatidylinositol-3 kinase like kinases |
| 出版年: | 2011
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| 发表日期: | 2011-03-24
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| 国家: | 美国
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| 语种: | 英语
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| 英文关键词: | low dose radiation
; phosphatidyl-inositol kinase like kinases
; ataxia telangiectasia mutated
; DNA dependent protein kinase
; DNA double strand breaks
; low linear energy transfer radiation
; gamma rays
; 2-dimensional and 3- dimensional human epiderm tissues
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| 中文主题词: | 铅
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| 主题词: | LEAD
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| 英文摘要: | It is increasingly realized that human exposure either to an acute low dose or multiple chronic low doses of low LET radiation has the potential to cause different types of cancer. Therefore, the central theme of research for DOE and NASA is focused on understanding the molecular mechanisms and pathways responsible for the cellular response to low dose radiation which would not only improve the accuracy of estimating health risks but also help in the development of predictive assays for low dose radiation risks associated with tissue degeneration and cancer. The working hypothesis for this proposal is that the cellular mechanisms in terms of DNA damage signaling, repair and cell cycle checkpoint regulation are different for low and high doses of low LET radiation and that the mode of action of phosphatidylinositol-3 kinase like kinases (PIKK: ATM, ATR and DNA-PK) determines the dose dependent cellular responses. The hypothesis will be tested at two levels: (I) Evaluation of the role of ATM, ATR and DNA-PK in cellular response to low and high doses of low LET radiation in simple in vitro human cell systems and (II) Determination of radiation responses in complex cell microenvironments such as human EpiDerm tissue constructs. Cellular responses to low and high doses of low LET radiation will be assessed from the view points of DNA damage signaling, DNA double strand break repair and cell cycle checkpoint regulation by analyzing the activities (i.e. post-translational modifications and kinetics of protein-protein interactions) of the key target proteins for PI-3 kinase like kinases both at the intra-cellular and molecular levels. The proteins chosen for this proposal are placed under three categories: (I) sensors/initiators include ATM ser1981, ATR, 53BP1, gamma-H2AX, MDC1, MRE11, Rad50 and Nbs1; (II) signal transducers include Chk1, Chk2, FANCD2 and SMC1; and (III) effectors include p53, CDC25A and CDC25C. The primary goal of this proposal is to elucidate the differences in cellular defense mechanisms between low and high doses of low LET radiation and to define the radiation doses where the cellular DNA damage signaling and repair mechanisms tend to shift. This information is critically important to address and advance some of the low dose research program objectives of DOE. The results of this proposed study will lead to a better understanding of the mechanisms for the cellular responses to low and high doses of low LET radiation. Further, systematic analysis of the role of PIKK signaling pathways as a function of radiation dose in tissue microenvironment will provide useful mechanistic information for improving the accuracy of radiation risk assessment for low doses. Knowledge of radiation responses in tissue microenvironment is important for the accurate prediction of ionizing radiation risks associated with cancer and tissue degeneration in humans. |
| URL: | http://www.osti.gov/scitech/servlets/purl/1009811
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| Citation statistics: |
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| 资源类型: | 研究报告
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| 标识符: | http://119.78.100.158/handle/2HF3EXSE/40417
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| Appears in Collections: | 过去全球变化的重建
影响、适应和脆弱性
科学计划与规划
气候变化与战略
全球变化的国际研究计划
气候减缓与适应
气候变化事实与影响
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| 1009811.pdf（88KB） | 研究报告 | -- | 开放获取 | | View
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| Recommended Citation: | |
. Cellular response to low dose radiation: Role of phosphatidylinositol-3 kinase like kinases. 2011-01-01.
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