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Update on Radiobiological Mechanisms at Low Doses/Dose-Rates

PL2-3. Update on Radiobiological Mechanisms at Low Doses/Dose-Rates. Mike Atkinson Institute of Radiation Biology Helmholtz-Zentrum München. A strategic research agenda for low-dose research in Europe. MELODI defines three priority areas:. Dose response relationships for cancer.

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Update on Radiobiological Mechanisms at Low Doses/Dose-Rates

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  1. PL2-3 Update on Radiobiological Mechanisms at Low Doses/Dose-Rates • Mike Atkinson • Institute of Radiation Biology • Helmholtz-Zentrum München

  2. A strategic research agenda for low-dose research in Europe

  3. MELODI defines three priority areas: Dose response relationships for cancer Individual sensitivity Non-cancer diseases

  4. What is the current state of the art ? Does the LNT model of DNA damage reflect biology? Are all men (and women!) created equal? Is the heart (and other organs) protected ?

  5. The following studies are supported by:

  6. Which response defines the dose- response curve ? The “dark matter” of the genome may modulate the radiation response. There are <1000 microRNAs in the genome, each of which can regulate <100 genes.

  7. Radiation regulates miRNA expression 2Gy, EA.hy926 cells

  8. miRNA processing required for survival

  9. Survival requires the miRNA response

  10. One pro-survival miRNA interacts with a complex protein network Rb MAPK NFkB Downregulated Upregulated

  11. Where are we going from here ? • How are the microRNAs regulated by radiation ? • What pathways do they influence, and why ? • Is this consistent with LNT ?

  12. What mechanisms determine individual sensitivity to radiation ? Sensitivity to radiation-induced cancer is under genetic influence. Mouse models allow the study of the mechanisms.

  13. Constitutive deletion of one copy of Rb1 confirms radiation sensitivity Rb1flox/+ cre-Col1 Rb1flox/+ p=0,0042

  14. Rapid loss of telomeres follows deletion of Rb1 in the osteoblast lineage T

  15. Telomere loss results in increased radiation-induced genomic instability Telomere attrition causes increased micronuclii and anaphase bridge formation after radiation *** ***

  16. Where are we going from here ? • How does Rb loss cause telomere erosion ? • Is genomic instability an initiating event ? • What other pathways influence individual radiation sensitivity ?

  17. What is the radiobiology behind the non-cancer effects of radiation ? • Radiation-induced chronic diseases include: • Cataract • Cardiovascular disease • Cognitive defects • Cancer • Are there common mechanisms involved ?

  18. Complex I Complex III Radiation effects changes to cellular function in the heart Downregulated Upregulated

  19. Dose dependent pathway alterations

  20. Where are we going from here ? • How does radiation influence pathways at low doses ? • Is there a common mechanism in cancer and non-cancer effects ?

  21. What does this mean for RP ? • 1) “New” processes occur after radiation. • Activation of the non-coding RNA transcriptome. • Alterations in pathways suggest a unified response. • Responses occur at 200mGy and are persistent. • 2) Susceptibility through genomic instability.

  22. Thank you for your attention Greetings from the UEFA Champions League 2012

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