Research on the Biological Effects of Heavy Charged Particles
of Different Energies

Participating countries and international organizations:

Armenia, Belarus, Bulgaria, Czech Republic, Cuba, Germany, Italy, Mongolia, Poland, Romania, Russia, Serbia, Slovakia, Vietnam.

Issues addressed and main goals of research:

Teoretical and experimental research on the biological effects of heavy charged particles of different energies at JINR's basic facilities.
The research and development will include:

• Research on the mechanisms of the development of DNA molecular damage and its repair in cultures of human and mammalian normal and tumor cells and in histological sections of tissues of different parts of animals' central nervous system after exposure to radiations of different LET.

• Research on the induction and molecular nature of different types of gene and structural mutations in mammalian and lower eukaryote cells depending on the radiation dose and LET, repair status, oxidative stress development, and genetic stability mechanisms.

• Research on the formation of complex chromosomal aberrations in normal and tumor cells of humans and laboratory animals. Evaluation of long-term consequences of exposure to radiations of different LET.

• Research on behavioral reaction disorders and pathomorphological changes in different structures of the brain, spinal cord, and critical organs and systems of irradiated laboratory animals. Conducting a search for new radioprotective drugs.

• Research on radiation-induced effects in microglia, oligodendrocytes and their precursors, and in the myelin sheath after exposure to densely ionizing radiation.

• Research on the mechanisms of the action of Ara-C and other radiosensitizers for the irradiation of different normal and tumor cell cultures and mice with transplanted tumors.

• Development of an hierarchy of mathematical models of radiation-induced biological effects that would describe the development of radiation-induced pathologies at different organization levels (from molecules to cell populations) and at different times (acute and long-term consequences).

• Improvement of accelerator-based radiobiological experiment procedures. Calculation of shieldings for new nuclear physics facilities; evaluation of the radiation conditions and development of radiation safety systems for them. Participation in the creation and tests of nuclear planetary science instruments.

Expected results in the current year:

• To identify the patterns of clustered DNA double-strand break (DSB) formation in human skin fibroblast nuclei and radioresistant U87 tumor cells after accelerated heavy charged particle exposure.

• To analyze the formation patterns and structure of complex clustered DNA damage by immunocytochemical staining of the repair proteins γH2AX, 53BP1, OGG1, and XRCC1 in human fibroblast nuclei after accelerated heavy ion exposure.

• To study the kinetics of clustered DNA DSB repair in human skin fibroblast nuclei and radioresistant U87 tumor cells after accelerated heavy charged particle exposure.

• To study the formation of different DNA damage types (single-strand breaks, base damage, and complex damage) in human fibroblast nuclei after accelerated heavy charged particle exposure.

• To assess the proportion of different DNA DSB repair pathways in human fibroblasts by immunocytochemical staining of the repair proteins RAD51 (HR) and DNA PKcs (NHEJ) after exposure to radiations of different quality.

• To study the formation and repair kinetics of clustered DNA DSBs in neuron precursor cell nuclei and mature neurons and in glial cells of the mammalian central nervous system (CNS) after accelerated heavy charged particle exposure — using the cell subpopulation markers NeuN, doublecortin, GFAP, BrdU, and calbindin.

• To perform experiments to study the expression of the genes encoding the repair proteins (RAD51, DNAPKcs, NBS1, MRE11, etc.) in human skin fibroblasts after accelerated heavy charged particle exposure.

• To study apoptosis induction in human skin fibroblasts and mammalian CNS neurons after accelerated heavy charged particle exposure.

• To study the expression of the genes encoding the proteins and caspases participating in apoptosis induction in human fibroblasts and nerve cells after accelerated heavy charged particle exposure.

• To study in vitro the formation and elimination of DNA DSBs in rat hippocampal cells using a primary hippocampal culture obtained from rats aged P0–P1.

• To identify the patterns of DNA DSB formation in mammalian CNS neurons after γ-ray and accelerated heavy ion exposure.

• To study clustered DNA DSB repair kinetics in mammalian CNS neurons after γ-ray and accelerated heavy ion exposure.

• To study the expression of the genes encoding the repair proteins (RAD51, DNA PKcs, NBS1, MRE11, etc.) in human fibroblasts after exposure to ionizing radiations with different characteristics.

• To continue research on the induction of structural mutations in yeast cells by radiations of different LET.

• To evaluate the action of respiratory impairment caused by mitochondrial DNA damage on sensitivity to radiation's damaging and mutagenic effects.

• To determine the characteristics of the mutations which decrease cells' radiosensitivity.

• To analyze yeast cells' radiosensitivity and genetic stability with the inactivated HAP1 phosphatase.

• To perform PCR analysis of structural damage in the hprt-gene in descendants of irradiated V79 cells.

• To compare structural and chromosomal damage spectra in radiation-induced mutants at different times after exposure.

• To perform metaphase analysis of long-term chromosomal damage after irradiation of Macaca mulatta monkeys' head with accelerated carbon and krypton ions.

• To study complex aberration induction in human normal (lymphocytes) and tumor (Cal 51 breast carcinoma) cells by photons, accelerated protons, and accelerated boron and nitrogen ions.

• To perform mFISH and standard metaphase analysis of the induction and elimination (3–6 months after exposure) of chromosomal aberrations in animal bone marrow cells and blood lymphocytes.

• To perform mFISH analysis of chromosomal aberrations induced in human peripheral blood lymphocytes by different types of radiation used in cancer therapy.

• To do mFISH karyotyping and analysis of structural and numerical chromosomal aberrations in different lines of human stem cells cultivated in vitro.

• To conduct premature chromatin condensation research on the induction of chromatin breaks in human normal (lymphocytes) and tumor (Cal 51 breast carcinoma) cells by γ-rays and accelerated protons and ions at different times after exposure.

• By protein extraction, to study inflammatory cytokine secretion in mouse brain homogenates after radiation exposure.

• To study the effect of cytosine arabinoside (Ara-C) on the survival of different mammalian and human normal and tumor cell lines by the criteria of clone formation and apoptosis after exposure to accelerated protons and γ-rays.

• To study the formation and elimination of γH2AX/53BP1 foci in cultures of U87 glioblastoma cells and cells of other radioresistant tumor lines after exposure to Bragg peak protons and γ-rays — under normal conditions and in the presence of Ara-C (±HU).

• To study DNA DSB formation in different parts of rodent CNS after in vivo irradiation with accelerated protons and γ-rays without radiomodifiers and in the presence of Ara-C (±HU).

• To study the kinetics of DNA single-strand break formation and transformation into DSBs for different types of normal and tumor cells irradiated in the presence and absence of Ara-C (± HU).

• To study the influence of Ara-C (± HU) on the radiosensitizing of normal and tumor cells for different exposure fractionation schemes and different cell hypoxia levels.

• To study modifications of small laboratory animals' behavioral reactions after HCP exposure using the drug AraC. To evaluate the pathological changes in different cell populations of the brain and the possibility of arresting such damage by the neuroprotective drug Cerebrolysin.

• To study morphological and functional changes in the CNS of SD rats and CD-1 mice after accelerated proton exposure.

• To continue research on pathogenesis in different mammalian tissues and organs after heavy charged particle exposure.

• To simulate DNA damage formation and repair after irradiation of normal and tumor cells with heavy charged particles of different energies.

• To simulate the growth of a tumor cell population after ionizing radiation exposure in the presence of DNA synthesis inhibitors.

• To develop a model of the growth of a tumor cell population after ionizing radiation exposure in the presence of metal nanoparticles.

• To continue molecular dynamics modeling of impairments of the structure and functioning of mutant and oxidized forms of proteins.

• To simulate radiation-induced neurogenesis and gliogenesis impairments and neuroinflammatory processes in CNS structures.

• To upgrade the Genome irradiation facility.

• To continue the design, fabrication, testing, and calibration of nuclear planetary science instruments using fast neuron generators at the LRB's test bench.

• To ensure the conduction of radiobiological experiments at the U-400M cyclotron (the Laboratory of Nuclear Reactions) and the medical beam of the Phasotron (the Laboratory of Nuclear Problems).

Collaboration