Assessing skin exposure by measuring DNA damage in skin cells

在人体意外暴露于辐照后，身体不同部位受到的剂量往往是高度不均匀的，皮肤区域受到的剂量可能比身体其他部位大得多。该项目的目标是开发可用于评估皮肤剂量的生物学方法，特别强调真皮和表皮细胞中的DNA损伤。我们之前的工作已经证明，在辐照后几周，在大鼠和人的皮肤成纤维细胞中检测微核（MN）是可能的。因此，我们的假设是，在因事故或恐怖分子煽动的事件而暴露后，可以使用小穿孔（3毫米）活检来估计皮肤剂量

Following accidental exposure of humans to irradiation, the dose to different parts of the body is often highly heterogeneous, and regions of the skin may receive substantially greater doses than other parts of the body. The goal of this project is to develop biological approaches that can be used to assess dose to the skin, with a particular emphasis on DNA damage in cells of the dermis and epidermis. Our previous work has demonstrated that it is possible to detect micronuclei (MN) in skin fibroblasts from both rats and humans taken weeks after irradiation. Thus, our hypothesis is that, following exposures due to accidents or terrorist-instigated incidents, it will be possible to estimate skin dose using a small punch (3 mm) biopsy that could be taken within a number of days or weeks after radiation exposure. The project will have four specific aims. The first aim builds on our previous studies and will refine our existing techniques to establish optimal methods to measure MN obtained from dermal fibroblasts using the smallest possible biopsy, working initially with mice and then with human skin. The second specific aim will be to investigate the potential for predicting the dose received by the skin, using measurements of radiation-induced foci (RIF) of proteins in the cell nuclei performed directly on sections obtained from skin biopsies. Again, the work will be initiated in skin from various different strains of mice (wild-type and with known genetic defects that influence radiosensitivity e.g. SCID and ATM knock-outs) and will be followed up in studies of human skin. The third specific aim will extend these techniques to examine exposure to high LET radiation (thermal neutrons). The focus of these studies will be to obtain information on RBE values relevant to accidental exposure using these techniques. The final specific aim will integrate these studies in skin with techniques being developed in other projects in the Center in animals given whole body irradiation or partial body irradiation, which simulate the conditions expected following exposure of humans in an accidental or terrorist-instigated radiation exposure; we will use the derived endpoints to examine the ability of mitigating agents developed in the program to mitigate against skin injury.