Accelerated heavy ions as a tool for solving problems in fundamental and space radiobiology

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1 Accelerated heavy ions as a tool for solving problems in fundamental and space radiobiology E. Krasavin Round Table 2 Italy-Russia@Dubna on SPACE PHISICS and BIOLOGY

2 On Earth - accelerators of heavy charged particles The sources of heavy ions with high energy In space cosmic rays from Galaxy Round Table 2 Italy-Russia@Dubna

3 Tracks of heavy ions in nuclear emulsion Z = 70 Si Z =14 PageTable 3 Round 2 Italy-Russia@Dubna Ca 20 Ti 22 Fe 26 Mammalian cell

4 Phasotron Protons with energy up to 660 MeV Page 4 Round Table 2 Italy-Russia@Dubna

5 U-400 M Heavy ions 7 Li Kr 9+ Energy up to 50 MeV/amu Round Page 5Table 2 Italy-Russia@Dubna

6 Synchrophasotron Protons, heavy ions Energy up to 10 GeV/amu Round Page 6Table 2 Italy-Russia@Dubna

7 Nuclotron Heavy ions Round Page 7Table 2 Italy-Russia@Dubna

8 The dose distribution of radiation in matter 1 unit of the dose 1 unit of the dose X-rays Fe ion Round Table 2 Italy-Russia@Dubna

9 Radial dose distribution G y/cm D o s e, Exp. Varma Katz.. Chatterjee Radial dose distribution in track of heavy ion ( 12 C, 2,57 MeV/u) Радиус трека, см r, cm Round Page 9Table 2 Italy-Russia@Dubna

10 What radiobiological problems can be solved at use of accelerated heavy particles? Round Table 2 Italy-Russia@Dubna Page 10

11 A. Heavy ions is a powerful tool for solving problems in radiation genetics Round Table 2 Italy-Russia@Dubna Page 11

12 The RBE problem block of DNA repair normal repair super fast repair DNA repair capacity of the living cells determines the type of RBE on LET dependence E.coli cells Page 12 Round Table 2 Italy-Russia@Dubna

13 Single DNA damage Single strand break Base damage Повреждени е основания Round Page Table 13 2 Italy-Russia@Dubna Повреждение сахара Sugar damage

14 Clustered DNA damage Double strand break of DNA Base damages Sugar damage Base damages Round Table 2 Italy-Russia@Dubna Page 14

15 Yield of clustered DNA damage as a function of LET 1E-10 Выход повреждений й/гр/дальтон Dalton Yield of damage/gy/d 1E-11 e - 1 H SSB + damage of opposite strand Base damage + sugar damage DSB SSB + damage of opposite strand Base damage + sugar damage DSB 4 He 12 C 1E-12 0, L E ЛПЭ, T, kev/µm кэв/мкм Round Page Table 15 2 Italy-Russia@Dubna

16 Comet assay for detection of DNA lesions mt D = 0 Gy D = 5 Gy D =10 Gy Dose, Gy Page 16 Round Table 2 Italy-Russia@Dubna D = 20 Gy D = 40 Gy D = 60 Gy

17 The mechanism of DSB DNA repair in human cells Ku70-Ku80 + ДНК PK связывает концы ДНК Rad50/Mre11/NBS1 резицирует 5 концы. 3 концы защищены RPA MRE11 protein Rad50/Mre11/NBS1 заполняет гэп Rad51соединяет 3 концы Rad51/52/54 обеспечивает поиск гомологии и миграцию ветвей XRCC4/lig4 зачищает и связывает концы Синтез гомологичных ветвей Нити восстановлены (репарация с ошибками) Завершение репарации лигированием концов и разрешение структуры Round Page Table 17 2 Italy-Russia@Dubna

18 DSB (γ-h2ax) in human cells after X-ray (А) and heavy ion irradiation (B) А B Round Page Table 18 2 Italy-Russia@Dubna

19 Radiation induced mutagenesis Gene mutation Guanine Structural mutation Page Round 19Table 2 Italy-Russia@Dubna

20 The frequency of gene and structural mutation induction after γ-ray and heavy ion irradiation а б 4 He Nm/N 10 Nm/N N 4 He20 12 C200 Dose, Gy Dose, Gy Round Table 2 Italy-Russia@Dubna Page 20

21 Induction of mutagenic DNA repair by heavy ions luciferase Round Table 2 Italy-Russia@Dubna Page 21 FMNH 2 + RCHO + O 2 FMN + RCOOH +H 2 O + hν

22 Mutagenic belt Mutagenic belt of heavy particle track Cor Page 22 Round Table 2 Italy-Russia@Dubna

23 Induction of deletion mutations by heavy ions - γ-rays; N 0 N m /N - 4 He (20 kev/µm); - 4 He (50 kev/µm); - 4 He (78 kev/µm); - 12 C (200 kev/µm) Dose, Gy Round Table 2 Italy-Russia@Dubna Page 23

24 RBE on LET dependence 3,2 2 R B E 3,0 2,8 2,6 2,4 2,2 2,0 1,8 1,6 1,4 1,2 1,0 0,8 x 1 x x x 3 x 1 gene mutations 2 deletions 3 lethal effect 0, L E T, kev/µm Page 24 Round Table 2 Italy-Russia@Dubna

25 Formation of unstable chromosomal aberration in human cells after heavy ion irradiation Unstable chromosomal aberration Aberrations/10 00 cells Block of cell division Dose, Gy Page 25 Round Table 2 Italy-Russia@Dubna

26 Formation of stable chromosomal aberrations in human cells after heavy ion irradiation Chromosome 1 Stable chromosomal aberration Translocations/10 00 cells Successful of cell division Dose, Gy Page 26 Round Table 2 Italy-Russia@Dubna

27 B. Accelerated heavy ions as a tool for modeling of biological action of space radiation Round Page Table 27 2 Italy-Russia@Dubna

28 The GCR flux The integral flux of GCR particles of carbon and iron groups equals to 10 5 part/cm 2 per year Particle flux density interplanetary space z per day per cm 2 Page 28

29 The energy spectrum of GCR and Nuclotron Page 29 Round Table 2 Italy-Russia@Dubna

30 Consequences of Galactic heavy ion action Induction of cancer; Formation of gene and structural mutations; Violation of visual functions: lesions of retina; cataract induction; CNS violation Round Page 30 Table 2 Italy-Russia@Dubna

31 Gardner tumors Relative Ri isk Harderian Gland Tumor Prevalence Gamma proton helium neon iron (600 MeV/u) iron (350 MeV/u) Iron ions γ-rays Dose, Gy Round Table 2 Italy-Russia@Dubna Page 31 Nelson, 2006

32 Skin cancer (rats) Round Page Table 32 2 Italy-Russia@Dubna Burns, Albert, 1986

33 RBE for carcinogenic effect of irradiation Round Table 2 Italy-Russia@Dubna Page 33

34 Worgul et al., 2006

35 Cataract ratio after irradiation by iron ions and X-rays Iron ions Iron ions Catara act ratio 1 X-rays RBE RBE = D x /D Fe Dose, Gy Dose, Gy Round Page Table 35 2 Italy-Russia@Dubna Worgul et al., 2006

36 Accelerated heavy ions and CNS Round Page 36 Table 2 Italy-Russia@Dubna

37 Cosmic ray hit frequencies in CNS critical areas A A B B CNS in General Fe 2 or 13% cells will be hit at least one Fe p particle 8 or 46% would be hit by at least one p particle with Z 15 p Every nucleus will be traversed by a proton once every 3 days and a alpha particle once every 30 days. Mixed Field Multi-hit FE ION TRACKS VISUALIZED BY MARKERS OF DNA DSBs (γh2ax) 0 cgy 50 cgy α e 100 cgy 200 cgy TRACK DIRECTION

38 Damage of large number cells in tissue by the single track of heavy ion Round Page Table 38 2 Italy-Russia@Dubna

39 In Vitro Neurotoxic Effects of 56 Fe Ions on Retinal Explants Arbitr. Units (pixel number/explant cgy 5 cgy 10 cgy 50 cgy 100 cgy 200 cgy Dose, cgy Round Page 39 Table 2 Italy-Russia@Dubna apoptosis Vazquez, 2006

40 Cognitive tests (Morris Water Maze) 56 Fe ions, 1 GeV/amu Control 1.5 Gy 1 month after irradiation Round Page 40Table 2 Italy-Russia@Dubna

41 Round Page 41 Table 2 Italy-Russia@Dubna NICA Project

42 Thank you for the attention Page 42

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