Mitigation of gastrointestinal acute radiation syndrome by promoting clusterin-mediated intestinal regeneration

ABSTRACT The radiation tolerance of the gastrointestinal (GI) tract can be exceeded in radiation accidents or in the case of nuclear warfare, resulting in a lethal GI acute radiation syndrome (GI-ARS). There are no current FDA- approved medical countermeasures to mitigate GI-ARS; thus, there is an urgent need to identify key mechanisms of repair and regeneration in the irradiated intestinal epithelium. We have shown that the regeneration of the intestinal epithelium in response to severe radiation injury is mediated through revival stem cells (revSCs), which are generated through fetal-like reprogramming and identified by a marker gene Clusterin (Clu) (the mouse ortholog of human CLU). Remarkably, whole animal deletion of Clu significantly sensitizes mice to GI-ARS, while GI-ARS in mice is significantly mitigated via treatment with exogenous mouse Clu protein starting 24 hours post-irradiation. In addition, our preliminary data suggest that the cGAS-STING pathway acts as an upstream regulator of Clu in the irradiated intestinal epithelium. Treatment of mice with a STING agonist MSA-2 starting 24 hours after irradiation significantly improves the regeneration of irradiated small intestines. Thus, the overall goal of this proposal is to develop novel mitigators of the GI-ARS that promote the regeneration of irradiated intestinal epithelium by targeting the STING-CLU axis. In Aim 1, we will define the mechanisms by which CLU mitigates the development of GI-ARS. In Aim 2, we will dissect the STING-CLU axis in regulating the development of GI-ARS. Successful completion of the proposed study will demonstrate the key role of CLU in promoting the regeneration of the intestinal epithelium following acute radiation injury in mice and human intestinal organoids. We anticipate that our findings will significantly impact the successful development of GI-ARS mitigators that target the STING-CLU axis.