Re-Purposing of Metformin as a Countermeasure for Radiation-Combined Injuries

University Of Pittsburgh At Pittsburgh, Pittsburgh PA

Investigators

Abstract

The changing geopolitical environment has increased the risk of mass population exposure to radiation, burn, and trauma induced combined injuries that can result in chronic fibrosis from a large-scale radiological incident improvised by a state or terrorist-owned nuclear device. There are a few countermeasures available that have limited efficacy. The long-term goal is to develop a potent therapy for combined injuries and its addition to the national stockpile. The overall objectives of this proposal are to (i) determine the dose of metformin that results in the best mitigation from combined injury in animal models and (ii) test the titrated dose from the animal study to mitigate combined injury in human skin tissue perfusion model and investigate the mechanism of metformin action. The central hypothesis is that metformin-based topical ointment can mitigate combined injuries by locally reducing cell damage, injury progression, and fibrosis by blocking TGFβ signaling. The rationale for this project is that determining the mechanism of action and preclinical optimization of metformin topical therapy in relevant preclinical animal and human tissue models offers a strong scientific framework for future clinical applications. The central hypothesis will be tested by pursuing two specific aims: 1) titrate metformin concentration that effectively mitigates combined injuries in animal models; 2) analyze the mitigation of metformin lotion for combined injuries and underlying mechanisms in human full-thickness skin perfusion model. Under the first aim, we will titrate the concentration of metformin in topical lotion efficacious to mitigate combined injury in mouse models using clinically relevant functional, histological, and molecular read-outs. Our second aim will focus on testing the best-mitigating dose from the animal studies in the human full-thickness perfusion model and investigate the possible role of AMPK-mTOR-TGFβ axis in metformin-mediated mitigation by employing gain and loss of gene function studies using pharmacological modulators of these pathways. The proposal is innovative, as it aims to perform a pre-clinical evaluation and investigate the mechanism of action of a non- invasive, off-the-shelf available therapeutic candidate cleared by the FDA for treating diabetes. The proposed research is significant because the successful completion of this project will provide strong scientific justification for starting a clinical trial as the next logical step in the therapy development process, FDA approval for use as a combined injury mitigator, and addition to the national stockpile.