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

基本信息

批准号：
8121172
负责人：
Shyam Biswal
金额：
$ 39.52万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
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/8121172
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 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

项目摘要

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/放射恐怖主义或事故的情况下，平民或紧急响应者暴露于电离辐射的风险很高。辐射暴露后产生的活性氧和电力物与造血免疫细胞的耗竭和粘膜屏障的丧失导致免疫反应受损，使机会性细菌诱发了个体感染，并加剧了辐射诱导的发病率，并导致sepsis驱动的发病率。迫切需要开发有效的疗法来减轻辐射和感染的协同作用，这些疗法可以转化为大规模的伤亡反应。我们的研究表明，氧化还原敏感的转录因子，核因子 - 炎症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。转录因子与其抑制剂的分离，通过电力或氧化剂的抑制剂KEAP1导致NRF2的核转运和抗氧化剂基因的转录诱导 - 谷胱甘肽途径，硫氧还蛋白途径，血红素氧酶-1，几种保护性途径，几种保护性途径，这些保护途径综合保护氧化应激和氧化应激损害。我们的研究提供了强烈的合理性，可以假设“增强NRF2途径将通过减轻氧化应激并改善放射线混合感染损伤后改善生存率来减轻多器官损伤”。 R21阶段将通过遗传方法（使用NRF2抑制剂，KEAP1）和小分子方法（使用小分子方法（使用强有力的NRF2激活剂，CDDO激活剂，Cddo-derivativator，Cddo-derivativativator，Cddo derivativativator，使用NRF2抑制剂），通过遗传方法（使用NRF2抑制剂的诱导缺失，CD-2- 2-2-2-2-2-2-22- Cyano-3,12-Dioxooleana-1,9（11）-dien-28- oic酸（CDDO）]，已接受I期临床试验）。基于使用NRF2激活剂进行介入辐射构成损伤的积极结果，R33期将重点介绍基于NRF2的最佳治疗方案和基于NRF2的预后生物标志物在小鼠模型中使用CDDO-ME进行基于NRF2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证明，将其焦点研究侧重于辐射后辐射后诱导的气候损伤。这些研究有望制定一种新的策略来减轻辐射联合损伤，该损伤可以用作目标人群的有效对策。第1页，共1个公共卫生相关性声明，迫切需要进行缓解和治疗辐射以及辐射联合感染损伤的新疗法，因为它们在放射线 /核战争 /事故情况下列出了巨大的公共卫生问题。除临床管理外，目前没有有效的疗法可以在核攻击期间转化为大规模因果关系。该应用的重点是制定通过靶向宿主防御因素来治疗辐射损伤的新型策略。