Development of lisinopril for post-exposure mitigation of late effects from a rad

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DESCRIPTION (provided by applicant): 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.