Radiation-induced bystander/non-targeted responses have been postulated to impact the estimation of health risks of exposure to ionizing radiation. Several mechanisms have been suggested to mediate the induced bystander effect. Among them, gap-junction communication has been shown to be a critical mediator. However, the aspects of junctional communication that affect propagation of radiation effects remain undefined. Using in vivo analytic approaches, the goal of this proposal is to exploit fundamental knowledge on permeability properties of gap junction proteins (connexins) to investigate the role of different connexins in propagating death-inducing (growth delay, apoptosis) or pro-survival effects (proliferative capacity) between irradiated and neighboring bystander tumor or normal cells. The central hypothesis is that the in vivo cellular microenvironment modulates gap-junction gating, and thereby propagation of biological effects between irradiated and bystander cells. These events are modulated by oxidative metabolism and DNA repair, and result in transient and persistent changes in affected bystander cells and their progeny. In four interrelated specific aims, we propose to investigate, in vivo, the effects of selective properties of connexin 26, connexin 32 and connexin 43 channels on the proliferative capacity of irradiated and bystander human cells. We will determine the effects of cyclooxygenase-2 (COX-2) signaling on the gap junction permeabilities that mediate the expression of bystander effects. We will also examine intercellular communication that may result in regulation of the DNA repair and checkpoint proteins, Rad9 and Translationally Controlled Tumor Protein (TCTP), in bystander cells. We will adapt novel technology to identify signaling metabolites transmitted between irradiated and bystander cells that lead to regulation of TCTP and Rad9 in bystander cells. With relevance to long term health risks, we will examine, in normal cells, altered signaling pathways and genomic instability in the progeny of surviving bystander cells. The proposed experiments build on in vitro preliminary data that integrate the 3 projects of this program together. These data unraveled novel in vivo interactions between connexins, TCTP, Rad9 and COX-2, and showed that signaling events mediated through intercellular communication promote these interactions.
The expression of bystander effects may impact the estimation of health risks of exposure to low doses of radiation from. diagnostic procedures and high doses received during therapy. By understanding the mechanisms underlying the role of intercellular communication in propagation of radiation-induced stressful effects, the outcome of this proposal may provide insight into potentiating the benefits of cancer radiotherapy by enhancing its killing effects and protecting against the propagation of damaging effects to healthy tissue.
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