Our research goal has been to mitigate radiation injuries to the lungs and kidneys. Mitigation is the use of a countermeasure after exposure to ionizing radiation but before symptoms develop. We have focused on a class of drugs, angiotensin converting enzyme (ACE) inhibitors, which have been used in the clinic for many indications. They have shown efficacy for mitigation of lethal radiation injuries to multiple organ in rats. We are now aiming to repurpose these drugs as mitigators for radiation-induced multiple organ failure, in survivors of acute hematological syndromes. Incidental use of these drugs by irradiated cancer patients decreased lung and kidney injuries. Since the ACE inhibitor lisinopril mitigates morbidity in rats when given 7 days after radiation, it fits the requirement of this U01 o be developed for post-exposure mitigation of injuries from a radiation or nuclear incident. We will address both purposes of this RFA. The first will be to further develop lisinopril by assessin efficacy post exposure in rats given total body irradiation. We will test lisinopril in combination with countermeasures proposed for the Strategic National Stockpile for use against acute radiation syndromes. We will also test lisinopril for mitigation after exposure to single low- and high-linear energy transfer irradiation (X-rays, neutron-gamma rays), and to radiation in combination with full thickness skin wounds that will occur from detonation of an improvised nuclear device. In addition we will evaluate efficacy in special populations (juvenile and geriatri rat models). For the second purpose of the U01, to elucidate the mechanism of action, we will use cutting-edge techniques to test a novel hypothesis to determine the molecular, cellular and physiological mechanism(s) of mitigation by lisinopril. These studies include next generation micro-ribonucleic acid sequencing (miRNA-Seq) and genetically altered (knock out) donor bone marrow transplantation in rats. Our results directly address the purposes of this RFA to advance lisinopril for licensure against radiation-induced multi-organ dysfunctions. We have organized an efficient as well as responsive research plan, team of experts and well trained personnel to meet our goals.
Our group was one of the first to demonstrate that injuries from irradiation can be mitigated by drugs when started after exposure. We have identified countermeasures that will mitigate radiation injuries to multiple organs. In this study, to advance these agents for use in a radiological or nuclear event, we will test them under conditions simulating an improvised nuclear device, and also investigate their mechanism of action which is required for FDA licensure.
|Medhora, Meetha; Haworth, Steven; Liu, Yu et al. (2016) Biomarkers for Radiation Pneumonitis Using Noninvasive Molecular Imaging. J Nucl Med 57:1296-301|
|Fish, Brian L; Gao, Feng; Narayanan, Jayashree et al. (2016) Combined Hydration and Antibiotics with Lisinopril to Mitigate Acute and Delayed High-dose Radiation Injuries to Multiple Organs. Health Phys 111:410-9|
|Medhora, Meetha; Gao, Feng; Glisch, Chad et al. (2015) Whole-thorax irradiation induces hypoxic respiratory failure, pleural effusions and cardiac remodeling. J Radiat Res 56:248-60|
|Moulder, John E; Cohen, Eric P; Fish, Brian L (2014) Mitigation of experimental radiation nephropathy by renin-equivalent doses of angiotensin converting enzyme inhibitors. Int J Radiat Biol 90:762-8|
|Sharma, Ashish; Fish, Brian L; Moulder, John E et al. (2014) Safety and blood sample volume and quality of a refined retro-orbital bleeding technique in rats using a lateral approach. Lab Anim (NY) 43:63-6|
|Gao, Feng; Fish, Brian L; Szabo, Aniko et al. (2014) Enhanced survival from radiation pneumonitis by combined irradiation to the skin. Int J Radiat Biol 90:753-61|
|Medhora, Meetha; Gao, Feng; Wu, Qingping et al. (2014) Model development and use of ACE inhibitors for preclinical mitigation of radiation-induced injury to multiple organs. Radiat Res 182:545-55|
|Gao, Feng; Fish, Brian L; Moulder, John E et al. (2013) Enalapril mitigates radiation-induced pneumonitis and pulmonary fibrosis if started 35 days after whole-thorax irradiation. Radiat Res 180:546-52|