Phosphoglycerate mutase 5 a mitochondrial serin/threonine phosphatase a novel target to mitigate GI-ARS.

Project Summary Currently, there is a need for strategies that mitigate gastrointestinal acute radiation syndrome (GI-ARS). The risk of large populations encountering radiation exposure is real and growing. Radiation induced oxidative stress plays a significant role in inducing radiation toxicity in intestinal epithelial cells. However, mitigation of GI-ARS requires mitigation of oxidative stress along with induction of epithelial regeneration by activation of WNT/β- catenin signaling. Mitochondrial serine/threonine phosphatase, phosphoglycerate mutase 5 (PGAM5), is involved in activation of oxidative stress along with inhibition of WNT/β-catenin signaling. PGAM5, located in the mitochondrial membrane, inhibits nuclear translocation of NRF2 and thereby represses NRF2-dependent anti- oxidant gene expression. Moreover, PGAM5 induces β-catenin degradation by dephosphorylating DVL2, a β- catenin destruction complex. We have observed that pharmacological inhibition of PGAM5 using a novel small molecule-based modulator at 24 hours post irradiation mitigates GI-ARS. We therefore hypothesize that PGAM5 could be a potential target for mitigation of radiation induced oxidative stress and activation of β-catenin signaling in intestinal stem cells. In this proposal, we will first examine the involvement of PGAM5 in intestinal stem cell radiosensitivity by using pharmacological or genetic modulation of PGAM5 (Specific Aim 1). Using a mouse model of GI-ARS and ex-vivo intestinal organoids, we will examine the involvement of PGAM5 in radiation induced oxidative stress and modulation of WNT/β-catenin signaling in ISCs. In specific aim 2, we will characterize the PGAM5 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 PGAM5 inhibitor will facilitate PGAM5 inhibitor as a medical countermeasure against radiation under the FDA’s Animal Rule.