Ciprofloxacin enhances DNA repair capacity after radiation combined injury

环丙沙星增强放射复合损伤后DNA修复能力

基本信息

批准号：
7682166
负责人：
Juliann Gong Kiang
金额：
$ 16.4万
依托单位：
HENRY M. JACKSON FDN FOR THE ADV MIL/MED
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：
2008-09-05 至 2010-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7682166
关键词：
Address Animal Experiments Animals Anthrax disease Antibiotics Apoptosis Apoptotic Bacterial DNA Bacterial DNA Topoisomerase II Biological Biological Assay Biological Markers Blood Blood Cells Bone Marrow Cell Cycle Cell Cycle Regulation Cell Line Cells Cessation of life Chromatin Ciprofloxacin DNA DNA Damage DNA Double Strand Break DNA Gyrase DNA Repair DNA Topoisomerase IV Data Drug Formulations Emergency Situation Eukaryotic DNA Topoisomerases II Event Exposure to Female Flow Cytometry Fluoroquinolones Future Gadd45a protein Gamma Rays Gene Expression Gene Proteins Gene Targeting General Population Genome Stability Genomics Genotoxic Stress Goals Hematology Hematopoietic Homologous Gene Hospitalization Human IACUC Immune system In Vitro Infection Inflammatory Response Injury Macaca mulatta Malignant Neoplasms Measures Mediating Medical Metric Modeling Modification Molecular Mus NBS1 gene Normal tissue morphology Nuclear Nuclear Accidents Pathologic Pathway interactions Pharmacodynamics Probability Production Property Proteomics Protocols documentation Quinolones RNA Radiation Radiation Injuries Radioprotection Reaction Reporting Research Ethics Committees SH2D3A gene Safety Sampling Sentinel Sepsis Signal Transduction Skin Statistical Data Interpretation Stress Surrogate Markers Therapeutic Effect Time Tissues Topoisomerase Topoisomerase II Topoisomerase-II Inhibitor Trauma Treatment Efficacy United States Food and Drug Administration Whole Blood Whole-Body Irradiation Work Wound Healing antimicrobial antimicrobial drug base biological adaptation to stress cost cytokine dirty bomb dosage effective therapy improved in vivo in vivo Model inhibitor/antagonist meetings nonhuman primate protein expression research study wound

项目摘要

DESCRIPTION (provided by applicant): This application addresses a major gap for medical treatment of radiation combined injuries (CI). Fluoroquinolones, like ciprofloxacin (CIP), are generally well-tolerated and commonly used for treating infections in the general population. The Food and Drug Administration (FDA) has recommended CIP for anthrax treatment, and it is maintained in the National Stockpile for specific human use in the event of a national emergency. We hypothesize that CIP exerts a radioprotective/therapeutic effect either indirectly through genotoxic stress response, or directly via ability to modify chromatin and/or inhibit eukaryotic topoisomerase (topo) II. CIP works by inhibiting bacterial DNA gyrase (bacterial topo II or topo IV), but has a slight inhibitory effects on eukaryotic topo II. Topo II catalyzes the double strand DNA break/religation reaction. Our rationale is based on: 1) mouse studies where CIP enhanced survival after 9.75 Gy total body irradiation (TBI) and CI mice and 2) increased DNA repair capacity in rhesus macaques that received 6.5 Gy TBI with CIP compared to TBI. Our long-term goals are to (1) clarify the pathologic mechanisms associated with combined injury (CI-radiation plus skin-wound trauma) and (2) assess the efficacy of selected antimicrobials for treating sepsis after CI. Our short-term goals are to 1) clarify the molecular mechanisms associated with apparent enhanced genomic stability conferred on TBI-CIP animals, and 2) to elucidate molecular pathways involved in increased survival after radiation injury (RI) and CI in B6D2F1 female mice. We will address these goals in three Specific Aims: Aim 1. Assess biological activities of CIP in human lymphoblastoid TK6 cells and a blood ex vivo pharmacodynamic assay, Aim 2. Measure CIP-molecular pharmacodynamics in mice in vivo by (a) quantify homologous genes and proteins for cell cycle, DNA repair, and apoptosis in hematopoietic, wound tissues following CI, and (b) assess DNA damage/ repair and apoptotic markers by FACS, and Aim 3. Discriminate changes in genomic stability post CI and CIP in hematopoietic samples for RI and CI by genomic challenge assay ex vivo. The R33 portion will be divided into 3 defined tasks: (a) radioprotective/therapeutic efficacy (b) mechanisms of action, and (c) genomic/proteonomic profiling. The increased understanding of immunomodulatory properties and activation of checkpoint pathways will facilitate greater utility of CIP, and of how quinolone antimicrobials might confer genomic stability, enhance wound healing, and improve survival. Ciprofloxacin (CIP) is in the Strategic National Stockpile for emergency use for anthrax treatment, and CIP formulation, safety, and manufacturing requirements are already fulfilled for human use by the Food and Drug Administration. In addition to antimicrobial activity, preliminary studies in non-human primates show that CIP increases the ability to fix DNA and induces the immune system, and these effects are, in all probability, beneficial as a bonus that might reduce future cancer deaths. In a scenario of a nuclear event, such as a dirty bomb or nuclear accident, where tens of thousands of people are potentially exposed to radiation-combined injuries, CIP may offer a cost-effective treatment that could significantly improve the chance of survival as anti-microbial agents that enhance production of mature blood cells and wound healing, thereby reducing the necessity of hospitalization at a time when medical facilities would be overwhelmed.

描述（由申请人提供）：该申请解决了放射复合损伤（CI）医疗治疗的主要空白。氟喹诺酮类药物，如环丙沙星 (CIP)，通常具有良好的耐受性，常用于治疗普通人群的感染。美国食品和药物管理局 (FDA) 推荐 CIP 用于炭疽治疗，并保存在国家库存中，供特定人类在国家紧急情况下使用。我们假设 CIP 通过基因毒性应激反应间接发挥辐射防护/治疗作用，或者直接通过修饰染色质和/或抑制真核拓扑异构酶 (topo) II 的能力发挥辐射防护/治疗作用。 CIP通过抑制细菌DNA旋转酶（细菌拓扑异构酶II或拓扑异构酶IV）发挥作用，但对真核拓扑异构酶II有轻微的抑制作用。 Topo II 催化双链 DNA 断裂/重新连接反应。我们的理由基于：1) 小鼠研究中，CIP 提高了 9.75 Gy 全身照射 (TBI) 和 CI 小鼠后的存活率；2) 与 TBI 相比，接受 6.5 Gy TBI 的恒河猴的 DNA 修复能力增加。我们的长期目标是 (1) 阐明与复合损伤（CI 辐射加皮肤创伤）相关的病理机制，以及 (2) 评估所选抗菌药物治疗 CI 后脓毒症的疗效。我们的短期目标是 1) 阐明与 TBI-CIP 动物基因组稳定性明显增强相关的分子机制，2) 阐明 B6D2F1 雌性小鼠辐射损伤 (RI) 和 CI 后存活率提高的分子途径。我们将通过三个具体目标来实现这些目标：目标 1. 评估 CIP 在人淋巴母细胞 TK6 细胞和血液离体药效学测定中的生物活性，目标 2. 通过 (a) 量化同源基因来测量小鼠体内 CIP 分子药效学CI 后造血、伤口组织中细胞周期、DNA 修复和细胞凋亡的蛋白质，以及 (b) 通过 FACS 评估 DNA 损伤/修复和细胞凋亡标记物，目标 3. 通过离体基因组攻击测定，区分 RI 和 CI 造血样品中 CI 和 CIP 后基因组稳定性的变化。 R33 部分将分为 3 个明确的任务：（a）辐射防护/治疗功效（b）作用机制，以及（c）基因组/蛋白质组分析。对免疫调节特性和检查点通路激活的更多了解将有助于 CIP 的更大效用，以及喹诺酮类抗菌药物如何赋予基因组稳定性、增强伤口愈合和提高生存率。环丙沙星 (CIP) 已列入国家战略储备，用于紧急治疗炭疽病，并且 CIP 的配方、安全性和生产要求已满足美国食品和药物管理局对人类使用的要求。除了抗菌活性之外，对非人类灵长类动物的初步研究表明，CIP 还可以增强修复 DNA 并诱导免疫系统的能力，这些作用很可能是有益的，可以减少未来的癌症死亡。在发生核事件（例如脏弹或核事故）的情况下，数万人可能受到辐射联合伤害，CIP 可以提供一种经济有效的治疗方法，可以显着提高生存机会-微生物制剂可增强成熟血细胞的产生和伤口愈合，从而在医疗设施不堪重负的情况下减少住院的必要性。

项目成果

期刊论文数量（11）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Brain Damage and Patterns of Neurovascular Disorder after Ionizing Irradiation. Complications in Radiotherapy and Radiation Combined Injury.

电离辐射后的脑损伤和神经血管疾病的模式。

DOI：
发表时间：
2021-07-01
期刊：
影响因子：
3.4
作者：
Gorbunov, Nikolai V;Kiang, Juliann G
通讯作者：
Kiang, Juliann G

Geldanamycin analog 17-DMAG limits apoptosis in human peripheral blood cells by inhibition of p53 activation and its interaction with heat-shock protein 90 kDa after exposure to ionizing radiation.

暴露于电离辐射后，格尔德霉素类似物 17-DMAG 通过抑制 p53 活化及其与热休克蛋白 90 kDa 的相互作用来限制人外周血细胞的凋亡。

DOI：
发表时间：
2011-09
期刊：
影响因子：
3.4
作者：
Fukumoto, Risaku;Kiang, Juliann G
通讯作者：
Kiang, Juliann G

A review of the impact on the ecosystem after ionizing irradiation: wildlife population.

电离辐射对生态系统影响的回顾：野生动物种群。

DOI：
发表时间：
2022
期刊：
影响因子：
2.6
作者：
Cannon, Georgetta;Kiang, Juliann G
通讯作者：
Kiang, Juliann G

Radiation Combined Injury: DNA Damage, Apoptosis, and Autophagy.

放射复合损伤：DNA 损伤、细胞凋亡和自噬。

DOI：
发表时间：
2010-04-30
期刊：
影响因子：
0
作者：
Kiang, Juliann G;Garrison, Bradley R;Gorbunov, Nikolai V
通讯作者：
Gorbunov, Nikolai V

Autophagy and mitochondrial remodelling in mouse mesenchymal stromal cells challenged with Staphylococcus epidermidis.

表皮葡萄球菌攻击的小鼠间充质基质细胞的自噬和线粒体重塑。

DOI：
发表时间：
2015-05
期刊：
影响因子：
5.3
作者：
Gorbunov, Nikolai V;McDaniel, Dennis P;Zhai, Min;Liao, Pei;Garrison, Bradley R;Kiang, Juliann G
通讯作者：
Kiang, Juliann G