Novel strategy to mitigate and treat radiation combined infection injury by targe

描述（由申请人提供）：在核/辐射恐怖主义或事故的情况下，平民或应急人员暴露于电离辐射的风险很高。由于造血免疫细胞的耗竭和粘膜屏障的丧失，辐射暴露后产生的活性氧和亲电试剂与免疫反应受损有关，使个体容易受到机会性细菌的继发性感染，并加剧败血症引起的辐射引起的发病率和死亡率。迫切需要开发有效的治疗方法来减轻辐射和感染的协同效应，这可以转化为大规模伤亡反应。我们的研究表明，氧化还原敏感转录因子，核因子-红细胞2 p45相关因子2 （NRF2）通过抑制氧化应激，对环境氧化剂和细菌感染引起的炎症性疾病具有保护作用。亲电试剂或氧化剂将转录因子与其抑制剂KEAP1分离，导致NRF2的核易位和抗氧化基因——谷胱甘肽途径、硫氧还蛋白途径、血红素加氧酶-1的转录诱导，这几种保护途径共同防止氧化应激和大分子损伤。我们的研究为假设“增强Nrf2通路可以通过减轻氧化应激来减轻多器官损伤，提高辐射联合感染损伤后的生存率”提供了强有力的依据。R21期将通过遗传方法（使用诱导缺失Nrf2抑制剂KEAP1）和小分子方法(使用强效Nrf2激活剂CDDO- me[2-氰基-3,12-二氧齐烷-1,9（11)-二烯-28-oic酸（CDDO）的甲酯衍生物，已进行I期临床试验）研究增强Nrf2通路以减轻辐射联合细菌感染损伤小鼠模型后多器官损伤和提高生存率的策略。基于使用Nrf2激活剂干预辐射联合损伤的积极结果，R33阶段将重点开发基于CDDO-Me的Nrf2治疗小鼠模型的最佳治疗方案和预后生物标志物，然后在非人灵长类动物模型中进行概念验证研究，重点研究辐射后诱导的胃肠道损伤。这些研究有望开发一种新的策略来减轻辐射复合损伤，可以作为目标人群的有效对策。在放射性/核战争/事故情景下，缓解和治疗辐射以及辐射联合感染损伤的新疗法是迫切需要的，因为它们提出了一个巨大的公共卫生问题。除了临床管理之外，目前还没有有效的治疗方法可以在核攻击期间转化为大规模因果关系。该应用侧重于通过靶向宿主防御因子来治疗辐射损伤的新策略的开发。

DESCRIPTION (provided by applicant): The risk of civilians or emergency responders being exposed to ionizing radiation is high in scenarios of nuclear/radiological terrorism or accidents. Reactive oxygen species and electrophiles generated after radiation exposure is involved in impaired immune response due to depletion of hematopoietic immune cells and loss of mucosal barriers, predisposing an individual to secondary infection by opportunistic bacteria and exacerbate radiation-induced morbidity and mortality driven by sepsis. There is an urgent need to develop effective therapies to mitigate synergistic effects of radiation and infection, which can be translated to mass casualty response. Our studies have shown that redox sensitive transcription factor, nuclear factor-erythroid 2 p45-related factor 2 (NRF2) protects against inflammatory disorders caused by environmental oxidants and bacterial infection by inhibiting oxidative stress. Dissociation of the transcription factor from its inhibitor, KEAP1 by electrophiles or oxidants causes nuclear translocation of NRF2 and transcriptional induction of antioxidant genes - glutathione pathway, thioredoxin pathway, heme oxygenase-1, several protective pathways that collectively protect against oxidative stress and macromolecular damage. Our research provides strong rational to hypothesize that "enhancing the Nrf2 pathway will mitigate multi-organ injury by attenuating oxidative stress and improve survival following radiation-combined infection injury". The R21 phase will investigate the strategy of enhancing the Nrf2 pathway to mitigate multi-organ injury and improve survival following radiation-combined bacterial infection injury in mice models by genetic approach (using inducible deletion of Nrf2 inhibitor, KEAP1) and small molecule approach (using a potent Nrf2 activator, CDDO-Me [methyl ester derivative of 2- cyano-3,12-dioxooleana-1,9(11)-dien-28-oic acid (CDDO)] that has undergone phase I clinical trial). Based on a positive outcome of intervening radiation-combined injury using Nrf2 activator, the R33 phase will focus on development of optimal treatment regimen and prognostic biomarkers of Nrf2 based therapy using CDDO-Me in mice model and then perform proof of concept studies in nonhuman primate model focusing on post-radiation induced gastrointestinal injury. These studies promise to develop a novel strategy to mitigate radiation- combined injury that can be used as an effective countermeasure in target population. Page 1 of 1 Public Health Relevance Statement Novel therapy for mitigating and treating radiation as well as radiation combined infection injury is urgently warranted because they present a huge public health problem in radiological/nuclear war /accident scenario. Other than clinical management, currently there are no effective therapies that can be translated to mass causality during a nuclear attack. This application is focused on development of a novel strategy for treating radiation injury by targeting a host defense factor.