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

靶向减轻和治疗放射复合感染损伤的新策略

• 批准号: 8308482
• 负责人: Shyam Biswal
• 金额: $ 27.91万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-08-21 至 2013-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8308482
• 关键词: 2-cyano-3,12-dioxoolean-1,9-dien-28-oic acid; Abdomen; Accidents; Acetaminophen; Acute; Aftercare; Antioxidants; Apoptosis; Area; Attenuated; Bacteremia; Bacteria; Bacterial Infections; Bacterial Translocation; Bioinformatics; Biological Markers; Bleomycin; Blood Cells; Blood Circulation; Brain; Burn injury; Calculi; Carcinogens; Cells; Cerebral hemisphere hemorrhage; Chronic; Clinical; Clinical Management; Colitis; Cytomegalovirus; DNA Damage; Data; Development; Dextran Sulfate; Disease; Dissociation; Dose; Drug Kinetics; Drug effect disorder; Emergency Situation; Endotoxins; Enzymes; Epithelial; Epithelial Cells; Esters; Ethical Issues; Etiology; Event; Failure; Fibrosis; Functional disorder; Gastrointestinal Injury; Gastrointestinal tract structure; Gene Expression; Genes; Genetic; Genomics; Glucose; Glutamate-Cysteine Ligase; Glutathione; Glutathione S-Transferase; Gram-Negative Bacteria; Gram-Positive Bacteria; Hematopoietic; Hematopoietic System; Host Defense; Human; Immune; Immune response; Immunohistochemistry; Incidence; Individual; Infection; Inflammation; Inflammatory; Injury; Integration Host Factors; Intestines; Ionizing radiation; Kidney; Lethal Dose 50; Ligation; Link; Liver; Longitudinal Studies; Lung; Maryland; Measurement; Modeling; Morbidity - disease rate; Mus; Myelosuppression; NADP; Natural regeneration; Nuclear; Nuclear Translocation; Organ; Organ failure; Outcome; Oxidants; Oxidation-Reduction; Oxidative Stress; Oxidoreductase; Pathway interactions; Permeability; Pharmaceutical Preparations; Pharmacodynamics; Phase; Phase I Clinical Trials; Phase II Clinical Trials; Pneumonia; Predisposition; Proteins; Proteomics; Protocols documentation; Pseudomonas aeruginosa; Public Health; Public Health Schools; Radiation; Radiation Injuries; Radiation Interaction; Radiation Syndromes; Reactive Oxygen Species; Readiness; Regulation; Reperfusion Injury; Research; Risk; Rodent; Sepsis; Serum; Severities; Specificity; Staging; Streptococcus; Streptococcus pneumoniae; Stress; Structure; Syndrome; Tamoxifen; Target Populations; Terrorism; Testing; Therapeutic; Thioredoxin; Time; Tissues; Toxic effect; Translating; Treatment Protocols; Universities; Villus; War; Western Blotting; Whole-Body Irradiation; Wild Type Mouse; base; biological systems; carcinogenesis; cigarette smoke-induced; combat; dosage; drug efficacy; effective therapy; efficacy testing; gastrointestinal; glutathione peroxidase; heme oxygenase-1; improved; inhibitor/antagonist; irradiation; lung injury; mortality; mouse model; multiorgan injury; new therapeutic target; nonhuman primate; novel; novel strategies; nuclear factor-erythroid 2; open wound; pre-clinical; prognostic; programs; public health relevance; radiation effect; research study; response; secondary infection; small molecule; synergism; transcription factor

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.

描述（由申请人提供）：在核/放射性恐怖主义或事故情况下，平民或应急响应人员暴露于电离辐射的风险很高。辐射暴露后产生的活性氧和亲电子试剂会因造血免疫细胞的耗竭和粘膜屏障的丧失而导致免疫反应受损，使个体容易受到机会性细菌的继发感染，并加剧由辐射引起的败血症的发病率和死亡率。迫切需要开发有效的疗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) 通过抑制氧化应激来预防由环境氧化剂和细菌感染引起的炎症性疾病。亲电子试剂或氧化剂将转录因子与其抑制剂 KEAP1 解离，导致 NRF2 核转位并转录诱导抗氧化基因 - 谷胱甘肽途径、硫氧还蛋白途径、血红素加氧酶-1，以及共同防止氧化应激和大分子损伤的几种保护途径。我们的研究为“增强 Nrf2 通路将通过减轻氧化应激来减轻多器官损伤并提高辐射联合感染损伤后的生存率”这一假设提供了强有力的理由。 R21阶段将研究增强Nrf2通路的策略，以通过遗传方法（使用Nrf2抑制剂KEAP1的诱导缺失）和小分子方法（使用有效的Nrf2激活剂CDDO-Me [2-甲基酯衍生物]，在小鼠模型中减轻辐射联合细菌感染损伤后的多器官损伤并提高生存率。 氰基-3,12-二氧杂环己烷-1,9(11)-dien-28-oic Acid (CDDO)]已进行I期临床试验）。基于使用 Nrf2 激活剂干预辐射联合损伤的积极结果，R33 阶段将重点开发在小鼠模型中使用 CDDO-Me 的最佳治疗方案和基于 Nrf2 的治疗的预后生物标志物，然后在非人类灵长类动物模型中进行概念验证研究，重点关注辐射后诱导的胃肠道损伤。这些研究有望开发出一种减轻辐射联合损伤的新策略，可作为目标人群的有效对策。第 1 页（共 1 页） 公共卫生相关性声明 迫切需要减轻和治疗辐射以及辐射联合感染损伤的新疗法，因为它们在放射/核战争/事故情况下提出了巨大的公共卫生问题。除了临床管理之外，目前还没有可以转化为核攻击期间大规模因果关系的有效疗法。该申请的重点是开发一种通过靶向宿主防御因子来治疗辐射损伤的新策略。