Damage signaling from irradiated to non-irradiated cells

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Broad long-term objective: To define the effects of low-dose/fluence ionizing radiation in human diploid cells, with a particular emphasis on non-targeted effects; that is effects occurring in bystander cells which do not receive a direct radiation traversal through the nucleus. The objective is based on the hypothesis that "Non-irradiated cells in the vicinity of cells traversed by ionizing radiation experience similar biological effects as the irradiated cells, and their response is a) dependent on cellular redox-state; b) mediated by the effect of connexin43 protein on gap- junction intercellular communication and not through other mechanisms; c) dependent on the nature of the molecule(s) communicated between irradiated and non-irradiated cells; and d) measurable damage, including DNA damage, occurs in the progeny of the bystander cells. To this end, changes in gene expression, induction of DNA damage and persistence of oxidative stress will be studied in: 1) Bystander cells neighboring those cells traversed by ionizing radiation in confluent density-inhibited cultured exposed to fluences of alpha-particles by which only a small fraction of cells in the exposed culture experience a particle traversal through the nucleus. 2) Bystander cells mixed with cells radiolabeled with the short-range beta-particle emitter tritium and seeded in sufficient numbers to achieve confluent monolayers. Specific aims: I) Characterize the role of altered redox-state in mediating the expression of biological effects in bystander non-irradiated cells. II) Determine that connexin43 mediates the bystander response through its role in gap function mediated intercellular communication and not through its effect on short- range diffusible factor(s). III) Characterize the nature of the molecules communicated between irradiated and non-irradiated cells by examining the role of different connexins in the bystander response. IV) Determine the persistence of stressful effects in affected bystander cells and their progeny. Significance and health-relatedness: Characterization of the mechanism that mediate the transmission of stressful effects from low- dose/fluence irradiated cells to non-irradiated bystander cells are directly relevant to the field of radiation protection. The results of these studies will contribute to the development of adequate models to estimate risks of low dose-radiation exposure, especially in the case of alpha-particle radiation induced lung cancer. They are also relevant to diagnostic and therapeutic nuclear medicine where radionuclides are being investigated to detect various diseases and treat cancer.