Radiation induced bystander effects have been demonstrated with a variety of endpoints using mammalian cell cultures as well as 3D human tissues. However, neither the mechanism nor the relevance of the bystander response to human health is clear. While gap junction communication and presence of soluble mediator(s) are known to play an important role in the bystander response, the precise signaling molecules have yet to be identified. The overall goals of this project are to define the incidence and mechanism of radiation-induced bystander mutagenic response in vivo (non-targeted response);to clarify the role of cyclooxygenase-2(COX-2) signaling pathways in the process;and to examine the incidence of genomic instability in bystander tissues in wild type and in genetic susceptible animals. The central testable hypothesis is that COX-2 mediates radiation induced bystander mutagenesis in vivo and that the bystander cells are genomically unstable in ATM homozygously mutated animals. A series of five inter-related specific aims are proposed to address these goals. The novel gpt delta ttansgenic mice and embryo fibroblasts from these animals will be used to conelate the findings under both in vitro and in vivo conditions. A small 1 cm by 1 cm zone in the lower abdominal area will be inadiated with graded doses of X-rays and the expression of COX-2 levels as well as incidence and types of Spi (deletions) and gpt (point mutations) mutations will be examined in the non-targeted lung and breast tissues. Bystander response as a result of nuclei and cytoplasmic targeting in MEF cells from wild type and COX-2knock out mice will be conducted with a microbeam to delineate specific gene signaling pathways. To further define genomic instability in bystander tissues, incidence of gpt and Spi mutations will be examined over a period of several weeks post-irradiation in wild type as well as y47Mknock out mice. Extensive program interaction with Projects 1 and 3 are planned in that the role of Rad9 (Project 1) and the connexin protein (TCTP, Project 3) in modulating COX-2 function will be examined. Radiation induced bystander effects represent a paradigm shift in our understanding of the basic radiobiological principle and target theory of ionizing radiation. A better understanding of the mechanism of the bystander effect is important for an accurate assessment of cancer risk associated with low dose radiation exposure.
It is now apparent that the target for heritable damage induced by ionizing radiation is not only larger than the DNA, but larger than the cell itself The demonstration of long term genomic instability among bystander cells from in vitro studies would imply increased cancer risk among radiotherapy and diagnostic radiology patients, particularly among genetically susceptible population. It is imperative, therefore, to have a better understanding of in vivo bystander genotoxic effects and mechanism for low dose radiation risk assessment.
|Azzam, Edouard I; Colangelo, Nicholas W; Domogauer, Jason D et al. (2016) Is Ionizing Radiation Harmful at any Exposure? An Echo That Continues to Vibrate. Health Phys 110:249-51|
|Gong, Xuezhong; Ivanov, Vladimir N; Hei, Tom K (2016) 2,3,5,6-Tetramethylpyrazine (TMP) down-regulated arsenic-induced heme oxygenase-1 and ARS2 expression by inhibiting Nrf2, NF-ÎºB, AP-1 and MAPK pathways in human proximal tubular cells. Arch Toxicol 90:2187-200|
|Hei, Tom K (2016) Response of Biological Systems to Low Doses of Ionizing Radiation. Health Phys 110:281-2|
|Panigrahi, Sunil K; Hopkins, Kevin M; Lieberman, Howard B (2015) Regulation of NEIL1 protein abundance by RAD9 is important for efficient base excision repair. Nucleic Acids Res 43:4531-46|
|Autsavapromporn, Narongchai; Plante, Ianik; Liu, Cuihua et al. (2015) Genetic changes in progeny of bystander human fibroblasts after microbeam irradiation with X-rays, protons or carbon ions: the relevance to cancer risk. Int J Radiat Biol 91:62-70|
|Brengues, Muriel; Gu, Jian; Zenhausern, Frederic (2015) Microfluidic module for blood cell separation for gene expression radiobiological assays. Radiat Prot Dosimetry 166:306-10|
|Wang, Tony J C; Wu, Cheng-Chia; Chai, Yunfei et al. (2015) Induction of Non-Targeted Stress Responses in Mammary Tissues by Heavy Ions. PLoS One 10:e0136307|
|Gong, Xuezhong; Ivanov, Vladimir N; Davidson, Mercy M et al. (2015) Tetramethylpyrazine (TMP) protects against sodium arsenite-induced nephrotoxicity by suppressing ROS production, mitochondrial dysfunction, pro-inflammatory signaling pathways and programed cell death. Arch Toxicol 89:1057-70|
|Chen, Hongxin; Goodus, Matthew T; de Toledo, Sonia M et al. (2015) Ionizing Radiation Perturbs Cell Cycle Progression of Neural Precursors in the Subventricular Zone Without Affecting Their Long-Term Self-Renewal. ASN Neuro 7:|
|Dong, Chen; He, Mingyuan; Tu, Wenzhi et al. (2015) The differential role of human macrophage in triggering secondary bystander effects after either gamma-ray or carbon beam irradiation. Cancer Lett 363:92-100|
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