Development of a radiation countermeasure with sex-dependent radiation response.

PROJECT SUMMARY/ABSTRACT The research goal is to understand the mechanism underlying sex-specific effects in the regulation of radiation response and to develop a novel radiation countermeasure that targets such differences. Radiation responses can vary between sexes. Women have a higher long-term risk of radiation-induced cancers than men. However, female mice reveal greater resistance to radiation and exhibit stronger short-term protective responses. Such differences in humans and rodents underscore the necessity for further research to uncover the underlying mechanisms and their implications for radiation biology and medicine. Radiation countermeasures are designed to reduce damages. Despite extensive research, only a few have received FDA approval. Challenges persist in addressing long-term radiation effects and understanding sex-related responses. Our published and preliminary studies showed female Lxn knockout (Lxn-/-) mice had increased hematopoietic stem/progenitor cell (HSPC) survival and regeneration in physiological condition by downregulating thrombospondin 1 (Thbs1). Lxn deletion enhances radiation-induced survival by mitigating hematopoietic-acute radiation response and delayed effects by upregulating Bcl-2. Surprisingly, the male Lxn-/- mice had no hematopoietic changes in physiological condition, which is mechanistically due to the sex-specific silence of Thbs1 gene expression. We screened a novel Lxn inhibitor that shows radiation mitigation effect in vitro and in vivo in female mice. We hypothesize that pharmaceutical and genetic inhibition of Lxn mitigates radiation injuries in a sex-dependent manner. Two aims will be proposed. Aim 1 is to determine the cellular and molecular mechanisms of Lxn deletion in radiation mitigation in male mice. Aim 2 is to determine whether Lxn inhibitor is a countermeasure with sex-specific radiation mitigation effect. The results will advance our understanding of the mechanisms underlying sex-specific regulation of radiation response and produce significant implications for accurate radiation risk assessments and targeted treatments in various radiation exposure scenarios.