Sex specific differences in intestinal radiosensitivity

Project Summary Role of sex as a confounder in radiation research and its implication in radiological and nuclear countermeasure development has not been addressed well. Currently, there is a need for strategies that mitigate Gastrointestinal acute radiation syndrome (GI-ARS). However, sex specific differences in intestinal radiosensitivity have not been determined. Intestinal epithelium is one of the most radiosensitive tissue due to their high self-renewal rate. Radiation-induced damage in intestinal epithelium results in loss of crypt progenitor cells, damage of crypt villus structure resulting in impaired mucosal barrier function, inflammation, bacterial influx and sepsis. Our previous study clearly demonstrated that repair and regeneration of intestinal stem cells (ISCs) is crucial to mitigate radiation-induced toxicity of intestinal epithelium and thereby mitigation of GI-ARS. We have observed that male intestinal epithelium is more radiosensitive compared female with higher level of mitochondrial oxidative phosphorylation, reactive oxygen species production and inflammation. However, these differences are not related to sex hormone as sex steroid hormones have no direct effect on intestinal epithelium. Mitochondrial ROS production is directly related to mitochondrial pyruvate transport and oxidation. We observed that expression of mitochondrial pyruvate carrier (MPC) and pyruvate oxidation is higher in male intestinal epithelium than female. Inhibition of MPC significantly reduces the mitochondrial ROS production, minimize radiation induced epithelial damage and mucosal inflammation and thereby mitigate GI-ARS in both sexes of mice. We, therefore, hypothesize that mitochondrial pyruvate transport could be a potential target for mitigation of GI-ARS. In this proposal we will first examine the involvement of mitochondrial pyruvate metabolism in sex specific differences in ISC radiosensitivity by using pharmacological or genetic modulation of MPC (Specific aim 1). Next, we will examine weather inhibition of MPC can mitigate radiation induced acute mucosal inflammation (Specific aim 2) and reduce sex specific differences in radiation induced mucosal inflammation. Finally, we will characterize the MPC inhibitor treatment with a determination of an optimum dose and schedule for mitigation of GI-ARS in both male and female mice. We will examine the general applicability of this strategy in young and aged animals. Determination of mechanism of action and dose optimization study of MPC inhibitor will facilitate MPC inhibitor as a medical countermeasure against radiation under the FDA’s Animal Rule.