SP26 Radiation stress

SP26 Dissecting genetic basis of radiation hormesis and testing effects of low dose ionising radiation on homeostasis of murine tissues

Project leader: Maria Ermolaeva

Background and previous work
The phenomenon of radiation hormesis (e.g. health benefits of low dose radiation treatment) has been long regarded as controversial for two major reasons: (a) lack of defined molecular mechanism and (b) lack of systematic analysis in animal models. As worldwide exposure to radioactive materials and to radiation of the sun grows progressively, studies of radiation hormesis increase in priority. We recently investigated effects of ionizing radiation (IR) and ultraviolet light (UV) on systemic homeostasis of the nematode C. elegans and found strong positive impact of radiation on proteostasis and on innate immunity. Homeostatic improvement was dependent on UV- and IR-induced DNA damage response in the stem cell-like germ line of the nematode and on systemic activation of MAP kinase-innate immunity-proteostasis cascade. Thus we outlined first putative molecular mechanism of radiation hormesis. Given that identified signalling components are highly conserved in evolution, a similar mechanism may also imply in mammals.

Specific aims and working programme
Aim 1: We will test whether (a) whole body exposure to low dose ionising radiation and (b) specific induction of mild DNA damage in stem cells will have similar beneficial effects in mice as they do in C. elegans. For the induction of mild DNA damage in stem cells we will utilise stem-cell specific inducible Cre lines which have off-target genotoxic properties at high levels of Cre expression. Mouse models of inducible organ degeneration (DSS-induced colitis, streptozotocin-induced diabetes and cardiotoxin-induced muscle injury) will be used to validate potential homeostatic benefits of radiation/DNA damage pre-treatment. 

Aim 2: We will continue studying genetic mechanisms of radiation hormesis by using C. elegans as a model system. Specifically we will perform reverse genetic experiments and random mutagenesis-based forward genetic screens to identify mutations that block UV- and IR-induced homeostatic improvements in the nematode. 

Aim 3: Innate immunity appears to be the central mediator of enhanced homeostasis upon UV and IR treatment. At the same time innate immune response is strongly affected by additional environmental inputs such as nutrients and metabolites. We will study dietary effects on radiation hormesis by using nematode as a model.