Autofluorescence is a tool to monitor radiation exposure and predict acute lethality - PROJECT SUMMARY / ABSTRACT Despite extensive investigations into the effects of ionizing radiation on normal tissues, there is currently no easy way to quickly determine the dose to which a person has been exposed and if they require intervention. In such scenarios time is of the essence and with that in mind we have developed a concept for a novel biodosimeter with a compelling solution; namely autofluorescence imaging. It is based on our experience in studying radiation-induced autofluorescence in murine and human models, and our understanding of its part in the aftermath of radiation exposure. We have strong evidence that redox re-balancing takes place in irradiated cells through metabolically driven antioxidant-repair pathways, and this is reflected in autofluorescence that mechanistically ties the initial damage to exposure dose and intrinsic cellular radiosensitivity. Our hypothesis is that radiation-induced autofluorescence can be used 1) as a surrogate for radiation dose and 2) to assess the extent of damage to predict lethality. Against this backdrop we propose to develop autofluorescence profiles of murine and human cells in vitro so as to build a biomarker platform that integrates meaningful radiation-induced signals expressed as autofluorescence and that can be used to estimate the likelihood of radiation damage and lethality from hematopoietic acute radiation syndrome in mice. Our goal is to extend existing knowledge on patterns of autofluorescence after irradiation, examine their tight time/dose constraints, and determine if they accurately predict cell and tissue radiosensitivity. In Aim 1, we will determine broad parameters focused on dose- response and time course of autofluorescence in vitro. This will guide Aim 2 where autofluorescence responses will be re-assessed in vivo and extended to non-invasive imaging and examination of tissue samples taken within a 7-day window after exposure, and built around proven, robust endpoints such as blood work and 30-day survival. Autofluorescence signals will be generated in radiosensitive and radioresistant mouse strains as part of Aim 3 with the aim of aligning it with intrinsic radiosensitivity. Redox-targeting tools are used throughout to dissect the radiation-ROS-autofluorescence axis. These aims are designed to achieve our ultimate goal of providing proof-of-concept that radiation-induced autofluorescence can be employed as a fast, cheap, and easy radiation biomarker. The study has broad relevance to radiation effects in living systems and it epitomizes the complex interaction between redox rebalancing, repair processes, and survival. We have assembled a team that combines expertise in radiation biology, redox biology, immunology, radiation physics and dosimetry, veterinary care and statistics to cover all aspects of this research.
