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

描述(申请人提供)：我们的研究目标一直是减轻对肺和肾脏的辐射损伤。缓解是在暴露于电离辐射之后但在症状出现之前使用对策。我们重点介绍了血管紧张素转换酶(ACE)抑制剂这类药物，这些药物已经在临床上应用了许多适应症。它们已显示出缓解大鼠多器官致命辐射损伤的效果。我们现在的目标是改变这些药物的用途，使其在急性血液综合征的幸存者中缓解辐射引起的多器官衰竭。辐射癌症患者偶尔使用这些药物可以减少肺和肾脏的损伤。由于ACE抑制剂赖诺普利在辐射后7天给药可减轻大鼠的发病率，因此它符合本U01的要求，可用于辐射或核事故的照射后减轻伤害。我们将解决这个RFA的两个目的。第一个将是通过评估接受全身照射的大鼠暴露后的疗效来进一步开发赖诺普利。我们将联合试验赖诺普利 并为应对急性辐射综合征的国家战略储备提出了对策。我们还将测试赖诺普利在暴露于单一的低和高线性能量转移照射(X射线、中子-伽马射线)以及与简易核装置爆炸造成的全层皮肤创伤联合照射后的缓解作用。此外，我们还将评估在特殊人群(幼鼠和老年鼠模型)中的疗效。对于U01的第二个目的，为了阐明作用机制，我们将使用尖端技术测试一个新的假说，以确定赖诺普利缓解的分子、细胞和生理机制(S)。这些研究包括下一代微核糖核酸测序(miRNA-Seq)和大鼠的基因改变(敲除)捐赠者骨髓移植。我们的结果直接解决了这种RFA的目的，即推进赖诺普利用于治疗辐射诱导的多器官功能障碍的许可。我们组织了一支高效且反应迅速的研究计划、专家团队和训练有素的人员来实现我们的目标。

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.