Post-irradiation intervention to mitigate and treat chronic renal injuries

该项目基于这样一种假设，即某些类型的放射性恐怖主义事件之后会发生肾损伤，而且这种损伤既可以减轻，也可以治疗。我们使用的是最近NCI研讨会通过的惯例：“缓解”是指在辐射后但在辐射损伤的病理生理学证据出现之前开始有效的治疗；而“治疗”是指在辐射损伤的病理生理学证据出现之后开始有效的治疗。我们使用大鼠全身照射(TBI)模型证明了血管紧张素转换酶(ACE)抑制剂和血管紧张素II(ALL)1型受体拮抗剂(AT1受体拮抗剂)在减轻和治疗放射性肾损伤方面是有效的。我们之前的研究使用了类型的 放射肿瘤学和骨髓移植(BMT)中使用的分次高剂量率放射治疗方案旨在了解损伤的病理生理学基础，并经常使用尚未批准用于人类的制剂。拟议的研究将使用最有可能出现在放射性恐怖主义事件中的辐射计划类型(高剂量率或低剂量率下的单剂量)，并将重点放在开发适合临床使用的产品上。这项提案的具体目的是：证明卡托普利(FDA批准的ACE抑制剂)和氯沙坦(FDA批准的AT1阻滞剂)可以用于减轻和治疗可能由放射性恐怖主义引起的放射性肾损伤；确定这些药物是否通过抑制慢性氧化应激发挥作用；以及确定体外肾小球渗漏试验是否可以 可作为高通量筛选工具，用于寻找新的放射性肾损伤缓解剂。总而言之，实验研究表明，辐射引起的肾损伤是可以治疗的。该项目的目标是将这些实验方法中的一种或多种应用于临床实践。

This project is based on the hypothesis that renal injury will occur after certain types of radiological terrorism events, and that this injury can be both mitigated and treated. We are using the convention adopted by recent NCI workshops that: "mitigation" refers to therapies that are effective when begun after irradiation, but before there is pathophysiological evidence of radiation injury; and "treatment" refers to therapies which are effective when begun after pathophysiological evidence of radiation injury is present. We have used a rat total body irradiation (TBI) model to demonstrate that angiotensin converting enzyme (ACE) inhibitors and angiotensin II (All) type-1 receptor antagonists (AT1 blockers) are effective for the mitigation and treatment of radiation-induced renal injury. Our previous studies have used the types of fractionated high-dose-rate radiation schedules that are used in radiation oncology and bone marrow transplantation (BMT), have been oriented towards understanding the pathophysiological basis of the injury, and have often used agents that are not yet approved for human use. The proposed studies will use the types of radiation schedules most likely to present in radiological terrorism events (single doses at high or low dose rates) and will focus on developing products suitable for clinical use. The specific aims of this proposal are to: demonstrate that captopril (an FDA-approved ACE inhibitor) and losartan (an FDA-approved AT1 blocker) can be used to both mitigate and treat the radiation-induced renal injuries that could arise from radiological terrorism; determine whether these agents are acting via suppression of chronic oxidative stress; and determine whether an in vitro glomerular leakage assay can be used as a high through-put screening tool for finding new mitigators of radiation-induced renal injury. In summary, experimental studies suggest radiation-induced renal injury can be treated. The goal of this project is to bring one or more of these experimental approaches into clinical practice.