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：
8121916
负责人：
Juliann Gong Kiang
金额：
$ 38.12万
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 2013-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8121916
关键词：
Address 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 Double Strand Break DNA Gyrase DNA Repair DNA Topoisomerase IV Drug Formulations Emergency Situation Eukaryotic DNA Topoisomerases II Event Female Flow Cytometry Fluoroquinolones Future Gadd45a protein Gene Proteins Gene Targeting General Population Genome Stability Genomics Genotoxic Stress Goals Hematopoietic Homologous Gene Hospitalization Human Immune system In Vitro Infection Injury Macaca mulatta Malignant Neoplasms Measures Medical Molecular Mus NBS1 gene Normal tissue morphology Nuclear Nuclear Accidents Pathologic Pathway interactions Pharmacodynamics Probability Production Property Proteomics Quinolones Radiation Radiation Injuries Radioprotection Reaction Safety Sampling Sentinel Sepsis Skin 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 effective therapy improved in vivo nonhuman primate protein expression 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.

描述（由申请人提供）：本申请纠正了放射线联合伤害（CI）的医疗治疗的主要差距。氟喹诺酮类（如环丙沙星（CIP））通常具有良好的耐受性，通常用于治疗普通人群的感染。食品药品监督管理局（FDA）建议对CIP进行炭疽治疗，并在国家紧急情况下将其保留在国家库存中，以供特定的人类使用。我们假设CIP通过遗传毒性应力反应间接发挥放射性保护性/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的能力直接发挥作用。 CIP通过抑制细菌DNA回旋酶（细菌TOPO II或TOPO IV）而起作用，但对真核托普II具有轻微的抑制作用。 Topo II催化双链DNA断裂/宗教反应。我们的理由基于：1）小鼠研究，其中CIP在9.75 Gy总体照射（TBI）和CI小鼠后增强了生存率，以及2）与TBI相比，使用CIP接收6.5 Gy TBI的恒河猕猴中的DNA修复能力提高了DNA修复能力。我们的长期目标是（1）阐明与损伤联合损伤相关的病理机制（CI辐射加上皮肤创伤），（2）评估选定的抗菌药物在CI后治疗败血症的功效。我们的短期目标是1）阐明与TBI-CIP动物赋予的明显增强的基因组稳定性相关的分子机制，以及2）阐明在B6D2F1雌性小鼠B6D2F1中涉及增加生存率（RI）和CI的分子途径。 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)通过FACS评估DNA损伤/修复和凋亡标记，而AIM 3。通过基因组挑战测定法进行了CI后CI和CI的基因组稳定性变化，并在造血样品中进行CIP的CIP变化。 R33部分将分为三个定义的任务：（a）放射保护/治疗功效（b）作用机理，以及（c）基因组/蛋白质学分析。对免疫调节特性的了解和检查点途径的激活将有助于更大的CIP效用，以及喹诺酮抗菌剂如何赋予基因组稳定性，增强伤口愈合并提高存活率。