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Accession Number DE2012-1009811
Title Cellular Response to Low Dose Radiation: Role of Phosphatidylinositol-3 Kinase like Kinases.
Publication Date Mar 2011
Media Count 12p
Personal Author A. S. Balajee J. A. Meador Y. Su
Abstract 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.
Keywords Cancer
Carcinogens
Cells
Damage
DNA
Ionizing radiations
Malignant carcinomas
Phosphotransferases
Proteins
Radiation doses
Repair
Research programs
Risk assessment

 
Source Agency Technical Information Center Oak Ridge Tennessee
NTIS Subject Category 57V - Radiobiology
57F - Cytology, Genetics, & Molecular Biology
Corporate Author New York Univ. Medical Center, NY.
Document Type Technical report
Title Note N/A
NTIS Issue Number 1302
Contract Number DE-FG02-05ER64055

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